JP4980715B2 - Tricyclic heterocyclic compounds, compositions and methods for treating cancer or viral diseases - Google Patents

Abstract

The present invention relates to novel Triheterocyclic Compounds, compositions comprising a Triheterocyclic Compound, and methods useful for treating or preventing cancer or a neoplastic disorder comprising administering a Triheterocyclic Compound. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a cancer cell or neoplastic cell, treating or preventing a viral infection, or inhibiting the replication and/or infectivity of a virus.

Description

1. Field of the Invention The present invention relates to a tricyclic heterocyclic compound, a composition comprising the tricyclic heterocyclic compound, and a cancer or neoplasm comprising administering an effective amount of the tricyclic heterocyclic compound. The present invention relates to a method useful for treating or preventing a disease (neoplastic disease). The compounds, compositions and methods of the present invention include:
To treat or prevent cancer or neoplastic diseases, to inhibit the growth of cancer cells or neoplastic cells (neoplastic cells), to treat or prevent viral infections, It can also be used to inhibit replication or infectivity.

[Related applications]
This application claims the benefit of US patent application Ser. No. 60 / 474,741 filed May 30, 2003, the entire disclosure of which is incorporated herein by reference in its entirety.

[Background technology]
2 BACKGROUND OF THE INVENTION 2.1 Cancer and neoplastic diseases Cancer affects approximately 20 million adults and children worldwide, and more than 9 million new cases will be diagnosed this year. (International Cancer Institute (International A
genency for Research on Cancer), www. irac. f
r). According to the American Cancer Society, approximately 563100 Americans are expected to die from cancer during the year, surpassing 1500 per day. In the United States alone, nearly 5 million lives have been lost due to cancer since 1990, and about 12 million new cases have been diagnosed.

Currently, cancer treatment requires surgery, chemotherapy and / or radiation therapy to eradicate the patient's neoplastic cells (eg, Stockdale, 1998).
Year, “Principles of Cancer Patient Management
nt ", Scientific American: Medicine, vol. 3. See, Rubenstein and Federman, Chapter 12, Section IV). All of these approaches pose significant penalties for the patient. For example, surgery may be contraindicated depending on the patient's health or may not be accepted by the patient. In addition, it may not be possible to completely remove neoplastic tissue by surgery. Radiation therapy is only effective when the neoplastic tissue being irradiated is more sensitive to radiation than normal tissue, and radiation therapy often has serious side effects (
Ibid). With respect to chemotherapy, there are various chemotherapeutic drugs that can be utilized to treat neoplastic diseases. However, despite the availability of various chemotherapeutic drugs, chemotherapy has a number of drawbacks (eg, Stockdale,
1998, “Principles Of Cancer Pati ...
game ", Scientific American Medicine, vol.
. 3. Rubenstein and Federman
), Chapter 12, Section 10). Almost all chemotherapeutic drugs are toxic and chemotherapy is
Serious and often dangerous side effects such as severe nausea, bone marrow suppression, and immunosuppression.
In addition, many tumor cells have or become resistant to chemotherapeutic drugs through multidrug resistance.

The Tamura et al patent document (Japanese Patent Publication No. 05-086374) discloses metacycloprodigiosin and / or prodigiosin 25C as useful for treating leukemia, but L-5178Y cells in vitro. Only data on prodigiosin 25C activity against is provided. Hirata et al. (Patent Document 1)
2) discloses the use of cycloprodigiosin as a vacuolar ATPase proton pump inhibitor and states that cycloprodigiosin may have anti-tumor enhancing activity. Hirata et al. (JP 10-120563 A) discloses the use of cycloprodigiosin as an immunosuppressant and as an apoptosis inducer as a therapeutic agent for leukemia. Japanese Patent Publication No. 61-034403 granted to Kirin Brewery Co., Ltd. describes prodigiosin for prolonging the life of leukemia mice. Boger
r) non-patent literature (J. Org. Chem. 1988, Vol. 53, 1405-1415).
Page) discloses the in vitro cytotoxic activity of prodigiosin, prodigiosene and 2-methyl-3-pentylprodigiosene against mouse P388 leukemia cells. National Cancer Institute (National Cancer Institute)
e) (Developmental Therapeutics Pr of NCI / NIH
ogram website) discloses data obtained from human tumor cell line screening results, including butylcycloheptyl-prodiginin H
Cl screening is also included. However, this screening does not indicate that the screening compound is selective for cancer cells (eg, compared to normal cells).

Accordingly, there is a great need in the art for new compounds and compositions and methods that are useful for treating cancer or neoplastic diseases with low or no side effects as described above. Furthermore, there is a need for cancer treatments that provide cancer cell specific therapies with high specificity and low toxicity.

2.2 Viruses and diseases In addition to cancer, a vast number of human and animal diseases are derived from virulence and opportunistic virus infections (Belshe ed., 1984, “Textbook of Huma.
n Virology ", PSG Publishing, Littleton, Massachusetts, USA (
PSG Publishing)). A wide range of tissue viral diseases, including the respiratory tract, CNS, skin, urogenital tract, eye, ear, immune system, gastrointestinal tract, and musculoskeletal system, affect a vast number of people of all ages (Wyngarden and Smith) (Smith),
1988, “Cecil Textbook of Medicine, 18th Edition”, W. B. Sanders, Inc., Philadelphia (WB)
Saunders), see Table 328-2 on pages 1750-1753).

Despite considerable efforts to design effective antiviral therapies
Virus infections continue to threaten millions of lives worldwide. Attempts to develop antiviral drugs typically focus on several stages of the viral life cycle (eg,
Mitsuya H. et al., 1991, FASEB J
. 5: See pages 2369-2381 (Study on HIV)). However, a common drawback associated with the use of many current antiviral drugs is the deleterious side effects of antiviral drugs, such as toxicity to infected persons or resistance by certain virus strains.

Accordingly, there is a need in the art for antiviral compounds, compositions and methods that allow for safe and effective treatment of viral diseases without the aforementioned drawbacks.
Any reference cited or specified in [Background Art] of this application is not an admission that such reference is available as prior art to the present invention.

There is a great need in the art for new compounds and compositions and methods that are useful for treating cancer or neoplastic diseases with low or no such side effects.
Furthermore, there is a need for cancer treatments that provide cancer cell specific therapies with high specificity and low toxicity.

There is a need in the art for antiviral compounds, compositions and methods that allow for safe and effective treatment of viral diseases without the aforementioned drawbacks.

3 SUMMARY OF THE INVENTION The present invention provides a compound of formula (Ia):

And a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), _- C 2 ~C ₈ alkenyl, _-C 2 -C ₈ alkynyl, _-C 3 -C
₁₂ cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -OR ₁₄ ,-
_{O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (CH
_{2) n -R 14, -O-} C (O) OR 14, -O-C (O) NHR 14, -O-C (O)
N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR _1
4 , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NH
_{SR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C (
S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , -C (S) OR
₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —N
R ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —
NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R
₃ and R ₄ or R ₄ and R ₅ together form a 5- to 9-membered ring with the carbon atom to which each is attached, provided that Q ₃ is —C (R ₅ ) — and When m = 0, R
₅ is not H;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), - _{O-benzyl, -OH, -NH 2, -NH (} C 1 ~C 5 _{alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N (phenyl) ₂ , —N
H (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 2 ~C 8 _{alkynyl, -OR 14, -O (CH 2} ) n OR 14, -C (O) R ₁₄ , —O—C (O) R _1
4 , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR
₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄
, —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC
_{(O) R 14, -NHSR 14} , -NHSOR 14, -NHS (O) 2 R 14, -O (C
_{H 2) n C (O)} O (CH 2) n CH 3, O-C (S) R 14, O-C (S) OR 14,
_{O-C (S) NHR 14} , O-C (S) N (R 14) 2, -C (S) OR 14, -C (S
) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S)
R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S
) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —NH (phenyl)
, —N (phenyl) ₂ , —NH (naphthyl), —N (naphthyl) ₂ , —CN, —NO ₂ ,
-N ₃ , -C ₁ -C ₈ alkyl, -O- (C ₁ -C ₈ alkyl),-(C ₁ -C ₈ alkyl) -OH, -C ₂ -C ₈ alkenyl, -C ₂ -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _heterocycle, -OR _14, -O (CH _{2
) N OR 14, -C (O} ) R 14, -O-C (O) R 14, -C (O) (CH 2) n -R
₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄
) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—
R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ ,
—NHSOR ₁₄ , —NHS (O) ₂ R ₁₄ , O—C (S) R ₁₄ , O—C (S) OR _1
4 , O—C (S) NHR ₁₄ , O—C (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C
(S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (
S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C
(S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
_{-O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (C
H ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O
) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR
₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —N
_{HSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C
(S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) O
_{R 14, -C (S) NHR} 14, -C (S) N (R 14) 2, -NHC (S) R 14, -
NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ ,
_{-NR 14 C (S) NHR 14} , -NR 14 C (S) N (R 14) 2 and _either, together with _{R 11} and _{R 12,} 5-membered together with the carbon atom to which each is attached to 9 Forming a member heterocycle;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more particular embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more particular embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - and _{and, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

The invention further provides a pharmaceutically acceptable carrier or vehicle and an effective amount of formula (Ia
):

And a pharmaceutically acceptable salt thereof, wherein: wherein
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), _- C 2 ~C ₈ alkenyl, _-C 2 -C ₈ alkynyl, _-C 3 -C
₁₂ cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -OR ₁₄ ,-
_{O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (CH
_{2) n -R 14, -O-} C (O) OR 14, -O-C (O) NHR 14, -O-C (O)
N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR _1
4 , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NH
_{SR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C (
S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , -C (S) OR
₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —N
R ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —
NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R ₃
And R ₄ or R ₄ and R ₅ together form a 5- to 9-membered ring with the carbon atom to which each is attached, provided that Q ₃ is —C (R ₅ ) — and m If = 0, R
₅ is not H;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), - _{O-benzyl, -OH, -NH 2, -NH (} C 1 ~C 5 _{alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N (phenyl) ₂ , —N
H (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 2 ~C 8 _{alkynyl, -OR 14, -O (CH 2} ) n OR 14, -C (O) R ₁₄ , —O—C (O) R _1
4 , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR
₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄
, —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC
_{(O) R 14, -NHSR 14} , -NHSOR 14, -NHS (O) 2 R 14, -O (C
_{H 2) n C (O)} O (CH 2) n CH 3, O-C (S) R 14, O-C (S) OR 14,
_{O-C (S) NHR 14} , O-C (S) N (R 14) 2, -C (S) OR 14, -C (S
) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S)
R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S
) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —NH (phenyl)
, —N (phenyl) ₂ , —NH (naphthyl), —N (naphthyl) ₂ , —CN, —NO ₂ ,
-N ₃ , -C ₁ -C ₈ alkyl, -O- (C ₁ -C ₈ alkyl),-(C ₁ -C ₈ alkyl) -OH, -C ₂ -C ₈ alkenyl, -C ₂ -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _heterocycle, -OR _14, -O (CH _{2
) N OR 14, -C (O} ) R 14, -O-C (O) R 14, -C (O) (CH 2) n -R
₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄
) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—
R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ ,
—NHSOR ₁₄ , —NHS (O) ₂ R ₁₄ , O—C (S) R ₁₄ , O—C (S) OR _1
4 , O—C (S) NHR ₁₄ , O—C (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C
(S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (
S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C
(S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl. , -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -N
H (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C (
O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC (
^{_{= NH 2 +) NH 2,}} -CN, -NO 2, N 3, -3 -membered to 9-membered heterocycle, _{-OR 14,} -
_{O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (CH
_{2) n -R 14, -O-} C (O) OR 14, -O-C (O) NHR 14, -O-C (O)
N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR _1
4 , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NH
_{SR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C (
S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , -C (S) OR
₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —N
R ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —
NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R ₁₁ and R
Together with ₁₂ form a 5- to 9-membered heterocycle with the carbon atom to which each is attached;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more specific embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - _{is, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

In another aspect, the present invention provides a method for treating cancer in a patient, said method comprising providing a patient in need of treatment to a compound having the above formula (Ia) or a pharmaceutical agent of the compound And administering an effective amount of an acceptable salt, wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R
_{6 to} R ₈ and R _{10 to} R ₁₃ are defined above for the compounds of formula (Ia).

In yet another aspect, the present invention provides a method for treating a virus or viral infection in a patient, said method comprising the steps of: a compound having formula (Ia) as defined above or a Administering an effective amount of a pharmaceutically acceptable salt of the compound, wherein Q ₁ -Q ₄ , R ₂ , R ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are of the formula (Ia ) As defined above.

In another aspect, the invention relates to a method that can be used to prepare a tricyclic heterocyclic compound having formula (Ia).
In one embodiment, the present invention provides compounds of formula (Ia):

In the presence of an organic solvent and a protic acid in the presence of formula (II):

And a compound of formula (iv):

Contacting with a compound of formula (Ia) for a time and at a temperature sufficient to prepare a compound of formula (Ia)
Where
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), —R _a is —H, —OH, —C ₁ -C ₈ alkyl, —
C ₂ -C ₈ alkenyl, _-C 2 -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) _n OR ₁₄ ,
_{-C (O) R 14, -O} -C (O) R 14, -C (O) (CH 2) n -R 14, -O-C
(O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O
) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—R ₁₄ , —SO
R ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ , —NHSOR _1
4 , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—C (S)
OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄
, —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR _1
4 C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR
₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —
_{NH 2, -CN, -NO 2,} -SH, -N 3, -C 1 ~C 8 alkyl, -O- _(C 1 ~C
₈ alkyl), _- C 2 -C ₈ alkenyl, _-C 2 -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered heterocycle, _{-OR 14,} - O (CH
_{2) n OR 14, -C (} O) R 14, -O-C (O) R 14, -C (O) (CH 2) n -
R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R _{1
4) 2, -C (O)} N (R 14) 2, -C (O) OR 14, -C (O) NHR 14, -S
_{-R 14, -SOR 14, -S (} O) 2 R 14, -NHC (O) R 14, -NHSR 14
, -NHSOR ₁₄ , -NHS (O) ₂ R ₁₄ , O-C (S) R ₁₄ , O-C (S) OR
₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , −
C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C
(S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄
C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R ₃ and R ₄
Or R ₄ and R ₅ together form a 5- to 9-membered ring with the carbon atom to which each is attached, provided that Q ₃ is —C (R ₅ ) — and m = 0. In some instances, R ₅ is H
not;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), - _{O-benzyl, -OH, -NH 2, -NH (} C 1 ~C 5 _{alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N (phenyl) ₂ , —N
H (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 2 ~C 8 _{alkynyl, -OR 14, -O (CH 2} ) n OR 14, -C (O) R ₁₄ , —O—C (O) R _1
4 , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR
₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄
, —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC
_{(O) R 14, -NHSR 14} , -NHSOR 14, -NHS (O) 2 R 14, -O (C
_{H 2) n C (O)} O (CH 2) n CH 3, O-C (S) R 14, O-C (S) OR 14,
_{O-C (S) NHR 14} , O-C (S) N (R 14) 2, -C (S) OR 14, -C (S
) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S)
R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S
) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —NH (phenyl)
, —N (phenyl) ₂ , —NH (naphthyl), —N (naphthyl) ₂ , —CN, —NO ₂ ,
-N ₃ , -C ₁ -C ₈ alkyl, -O- (C ₁ -C ₈ alkyl),-(C ₁ -C ₈ alkyl) -OH, -C ₂ -C ₈ alkenyl, -C ₂ -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _heterocycle, -OR _14, -O (CH _{2
) N OR 14, -C (O} ) R 14, -O-C (O) R 14, -C (O) (CH 2) n -R
₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄
) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—
R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ ,
—NHSOR ₁₄ , —NHS (O) ₂ R ₁₄ , O—C (S) R ₁₄ , O—C (S) OR _1
4 , O—C (S) NHR ₁₄ , O—C (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C
(S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (
S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C
(S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
_{-O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (C
H ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O
) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR
₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —N
_{HSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C
(S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) O
_{R 14, -C (S) NHR} 14, -C (S) N (R 14) 2, -NHC (S) R 14, -
NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ ,
_{-NR 14 C (S) NHR 14} , -NR 14 C (S) N (R 14) 2 and _either, together with _{R 11} and _{R 12,} 5-membered together with the carbon atom to which each is attached to 9 Forming a member heterocycle;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer in the range of 0-6.

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more specific embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - and _{and, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

  In another embodiment, the present invention provides compounds of formula (Ia):

Provides a method of preparing a compound having:
(A) in the presence of a substantially anhydrous aprotic organic solvent, formula (II):

And a compound of formula (v):

[Wherein M is Li, Na, K, Rb or Cs]
A compound of formula (vi):

Contacting with a time and temperature sufficient to prepare a compound of the formula: wherein M is defined as above;
(B) protonating the compound of formula (vi) with an H ⁺ donor at a time and temperature sufficient to prepare the compound of formula (Ia), wherein
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , C ₁ -C ₈ alkyl, —O— (C
₁ -C ₈ alkyl), _- C 2 ~C ₈ alkenyl, _-C 2 -C _{8 alkynyl,} C 3 _{-C 12}
Cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR} 14, -O (
_{CH 2) n OR 14, -C} (O) R 14, -O-C (O) R 14, -C (O) (CH 2)
_{n -R 14, -O-C (} O) OR 14, -O-C (O) NHR 14, -O-C (O) N (
R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ ,
-S-R ₁₄ , -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR
_{14, -NHSOR 14, -NHS (O} ) 2 R 14, O-C (S) R 14, O-C (S)
OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄
, —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR _1
4 C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR
₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R ₃ and R ₄ or R ₄ and R ₅ together, together with the carbon atom to which each is attached. Forms a 5- to 9-membered ring, provided that when Q ₃ is —C (R ₅ ) — and m = 0, R ₅ is H
not;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), - _{O-benzyl, -OH, -NH 2, -NH (} C 1 ~C 5 _{alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N (phenyl) ₂ , —N
H (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 2 ~C 8 _{alkynyl, -OR 14, -O (CH 2} ) n OR 14, -C (O) R ₁₄ , —O—C (O) R _1
4 , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR
₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄
, —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC
_{(O) R 14, -NHSR 14} , -NHSOR 14, -NHS (O) 2 R 14, -O (C
_{H 2) n C (O)} O (CH 2) n CH 3, O-C (S) R 14, O-C (S) OR 14,
_{O-C (S) NHR 14} , O-C (S) N (R 14) 2, -C (S) OR 14, -C (S
) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S)
R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S
) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₈ is —Y _m (R _d ), where R _d is —H, —OH, halogen, amino,
-NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl),
-N _(phenyl) 2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -
N ₃ , —C _{1 to} C ₈ alkyl, —O— (C _{1 to} C ₈ alkyl), — (C _{1 to} C ₈ alkyl) —OH, —C _{2 to} C ₈ alkenyl, —C _{2 to} C ₈ alkynyl. , _-C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} )
_{n OR 14, -C (O)} R 14, -O-C (O) R 14, -C (O) (CH 2) n -R 1
₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ )
₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—R
₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ , —
NHSOR ₁₄ , —NHS (O) ₂ R ₁₄ , O—C (S) R ₁₄ , O—C (S) OR ₁₄
, OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C (
S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S
) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (
S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
_{-O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (C
H ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O
) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR
₁₄ , —S—R ₁₄ —, —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —
_{NHSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
_{, -NR 14 C (S) NHR} 14, or a _{-NR 14 C (S) N (} R 14) 2, R 11
And R ₁₂ together form a 5- to 9-membered heterocycle with the carbon atom to which each is attached;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more specific embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - and _{and, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

The present invention further provides a pharmaceutically acceptable carrier or vehicle and an effective amount of formula (Ib)
:

Or a pharmaceutically acceptable salt thereof, wherein a compound comprising:
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , C ₁ -C ₈ alkyl, —O— (C
₁ -C ₈ alkyl), _- C 2 ~C ₈ alkenyl, _-C 2 -C _{8 alkynyl,} C 3 _{-C 12}
Cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR} 14, -O (
_{CH 2) n OR 14, -C} (O) R 14, -O-C (O) R 14, -C (O) (CH 2)
_{n -R 14, -O-C (} O) OR 14, -O-C (O) NHR 14, -O-C (O) N (
R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ ,
-S-R ₁₄ , -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR
_{14, -NHSOR 14, -NHS (O} ) 2 R 14, O-C (S) R 14, O-C (S)
OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄
, —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR _1
4 C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR
₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R ₃ and R ₄ or R ₄ and R ₅ together, together with the carbon atom to which each is attached. Forms a 5- to 9-membered ring, provided that when Q ₃ is —C (R ₅ ) — and m = 0, R ₅ is not H;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ and R ₈ are independently —Y _m (R _d ), where —R _d is —H, —OH,
Halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —
NH (phenyl), -N (phenyl) ₂ , -NH (naphthyl), -N (naphthyl) ₂ ,-
CN, —NO ₂ , —N ₃ , —C _{1 to} C ₈ alkyl, —O— (C _{1 to} C ₈ alkyl), — (
C ₁ -C ₈ alkyl) -OH, -O- benzyl, _-C 2 -C ₈ alkenyl, _-C 2 -C _8
Alkynyl, -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -CH 2 O (} CH 2) n OR 14, -O-C (O) R ₁₄ , -C (
_{O) (CH 2) n -R} 14, -C (O) R 14, -O-C (O) OR 14, -O-C (O
) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O)
OR ₁₄ , —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ ,
-NHC (O) R ₁₄ , -NHSR ₁₄ , -NHSOR ₁₄ , -NHS (O) ₂ R ₁₄ ,
OC (S) R ₁₄ , OC (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N
(R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂
, —NHC (S) R ₁₄ , —NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —N
HC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R
₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
—CH ₂ O (CH ₂ ) _n OR ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R
₁₄ , —C (O) R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—
C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O)
NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R _{14
, -NHSR 14, -NHSOR 14, -NHS} (O) 2 R 14, O-C (S) R 14,
_{O-C (S) OR 14} , O-C (S) NHR 14, O-C (S) N (R 14) 2, -C (
S) OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R _1
4 , —NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄
) ₂ , —NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R
₁₁ and R ₁₂ together form a 5- to 9-membered heterocycle with the carbon atom to which each is attached;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more specific embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - and _{and, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

In another aspect, the present invention provides a method for treating cancer in a patient, said method comprising the steps of: a compound having the above formula (Ib) or a pharmaceutically acceptable compound thereof Administering an effective amount of an acceptable salt, wherein Q ₁ -Q ₄ , R ₂ , R ₄ , R ₆ -R
₈ and R _{10 to} R ₁₃ are defined above for the compounds of formula (Ib).

In yet another aspect, the present invention provides a method for treating a virus or viral infection in a patient, wherein the method comprises a compound having the above formula (Ib) or a compound thereof in a patient in need of treatment. Administering an effective amount of a pharmaceutically acceptable salt of
_{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ are defined above for the compounds of formula (Ib).

The present invention further encompasses compounds having formula (II) and pharmaceutically acceptable salts thereof.

[Where:
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ and R ₈ are independently —Y _m (R _d ), where —R _d is —H, —OH,
Halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —
NH (phenyl), -N (phenyl) ₂ , -NH (naphthyl), -N (naphthyl) ₂ ,-
CN, —NO ₂ , —N ₃ , —C _{1 to} C ₈ alkyl, —O— (C _{1 to} C ₈ alkyl), — (
C ₁ -C ₈ alkyl) -OH, -O- benzyl, _-C 2 -C ₈ alkenyl, _-C 2 -C _8
Alkynyl, -C 3 _{-C 12} cycloalkyl, - phenyl, - _naphthyl, -C 7 _{-C 12}
(Phenyl) alkyl, -C ₇ -C ₁₂ (naphthyl) alkyl, -C ₇ -C ₁₂ (phenyl) alkenyl, -C ₇ -C ₁₂ (naphthyl) alkenyl, -C ₇ -C ₁₂ (phenyl)
_Alkynyl, -C 7 _{-C 12} (naphthyl) alkynyl, -3-membered to 9-membered heterocycle, -OR _1
4 , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O)
(CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C
(O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) N
_{HR 14, -S-R 14,} -SOR 14, -S (O) 2 R 14, -NHC (O) R 14,
_{-NHSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O
_{-C (S) OR 14, O} -C (S) NHR 14, O-C (S) N (R 14) 2, -C (S
) OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄
, —NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ )
₂ , —NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
_{-O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (C
H ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O
) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR
₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —N
_{HSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C
(S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) O
_{R 14, -C (S) NHR} 14, -C (S) N (R 14) 2, -NHC (S) R 14, -
NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ ,
_{-NR 14 C (S) NHR 14} , -NR 14 C (S) N (R 14) 2 and _either, together with _{R 11} and _{R 12,} 5-membered together with the carbon atom to which each is attached to 9 Forming a member heterocycle;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

A compound of formula (Ia), (Ib) or (II) or a pharmaceutically acceptable salt thereof (“
Tricyclic heterocyclic compounds ") are used to treat or prevent cancer or neoplastic disease in patients in need of treatment or prevention, to inhibit the growth of cancer cells or neoplastic cells, and to treat or prevent. Useful for inhibiting viral replication or infectivity to treat or prevent viral infections in patients in need.

The present invention further provides a method of treating or preventing cancer or neoplastic disease, wherein the method administers an effective amount of a tricyclic heterocyclic compound to a patient in need of such treatment or prevention. Made up of.

The present invention further provides a method of inhibiting the growth of cancer cells or neoplastic cells, the method comprising contacting a cancer cell or neoplastic cell with an effective amount of a tricyclic heterocyclic compound. .

The present invention further provides a method of treating or preventing viral infection, the method comprising administering to a patient in need of such treatment or prevention an effective amount of a tricyclic heterocyclic compound.

The present invention further provides a method of inhibiting viral replication or infectivity, comprising:
Contacting the virus or virus-infected cell with an effective amount of a tricyclic heterocyclic compound.

In another aspect, the invention relates to a method that can be used to prepare a tricyclic heterocyclic compound having formula (Ib).
In one embodiment, the present invention provides compounds of formula (Ib):

A method is provided for preparing a compound having the formula (II): in the presence of an organic solvent and a protonic acid, at a time and temperature sufficient to prepare a compound of formula (Ib):

And a compound of formula (iv):

[Wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ are defined above for the tricyclic heterocyclic compound of formula (Ib)]
Contacting with a compound of:

  In another embodiment, the present invention provides compounds of formula (Ib):

Provides a method of preparing a compound having:
(A) in the presence of a substantially anhydrous aprotic organic solvent, formula (II):

  A compound of formula (v):

[Wherein M is Li, Na, K, Rb or Cs]
A compound of formula (vi):

Contacting with a time and temperature sufficient to prepare a compound of the formula: wherein M is defined as above;
(B) protonating the compound of formula (vi) with an H ⁺ donor for a time and at a temperature sufficient to prepare the compound of formula (Ib):
[Wherein Q ₁ -Q ₄ , R ₂ , R ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are defined above for compounds of formula (Ib)].

  In another aspect, the present invention provides a compound of formula (II):

In the presence of an organic solvent, a base and a Ni or Pd catalyst at a time and temperature sufficient to produce a compound of formula (II).
Compounds of ii):

And a compound of formula (ii) or a compound of formula (iii):

Including contacting with:
[Wherein Q ₁ , Q ₄ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ are defined above for the tricyclic heterocyclic compound of formula (II), and R ₁₅ is independently , C ₁ -C ₈ alkyl, cycloalkyl or phenyl].

  In certain embodiments, the tricyclic heterocyclic compound is Compound 1:

Or a pharmaceutically acceptable salt thereof.
In other embodiments, the tricyclic heterocyclic compound is the tartrate salt of Compound 1.
In yet another embodiment, the tricyclic heterocyclic compound is the mesylate salt of compound 1 (methanesulfonate).

In yet other embodiments, the tricyclic heterocyclic compound is a prodrug of Compound 1. In a more specific embodiment, the prodrug of Compound 1 is Compound 66 or Compound 67 or a pharmaceutically acceptable salt thereof.

  The present invention relates to a compound of formula (Ic):

And a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —O—, —S— or —N (R ₁ ) —;
Q ₂ is —C (R ₃ ) — or —N—;
Q ₃ is —C (R ₅ ) — or —N—;
Q ₄ is —C (R ₉ ) — or —N—;
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _{8. alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n O
R ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ ,
_{-O-C (O) OR 14} , -O-C (O) NHR 14, -O-C (O) N (R 14) 2,
_{-C (O) N (R 14} ) 2, -C (O) OR 14, -C (O) NHR 14, -S-R 14
, -SOR ₁₄ , -S (O) ₂ R ₁₄ , -NHC (O) R ₁₄ , -NHSR ₁₄ , -NH
SOR ₁₄ , —NHS (O) ₂ R ₁₄ , —OS (O) ₂ O ⁻ , O—C (S) R ₁₄ , O—
C (S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S)
OR ₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ ,
_{-NR 14 C (S) R 14} , -NHC (S) NHR 14, -NHC (S) N (R 14) 2
, —NR ₁₄ C (S) NHR ₁₄ or —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ , R ₄ and R ₅ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), _- C 2 ~C ₈ alkenyl, _-C 2 -C ₈ alkynyl, _-C 3 -C
₁₂ cycloalkyl, -phenyl, -naphthyl, -3 to 9-membered heterocycle, -OR ₁₄ ,-
_{O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (CH
_{2) n -R 14, -O-} C (O) OR 14, -O-C (O) NHR 14, -O-C (O)
N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR _1
4 , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NH
_{SR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C (
S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , -C (S) OR
₁₄ , —C (S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —N
R ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —
NR ₁₄ C (S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ , or R
₃ and R ₄ or R ₄ and R ₅ together form a 5- to 9-membered ring with the carbon atom to which each is attached;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C
Be ₁ -C ₈ alkyl);
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (
C ₁ -C ₈ alkyl), - _{O-benzyl, -OH, -NH 2, -NH (} C 1 ~C 5 _{alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N (phenyl) ₂ , —N
H (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 2 ~C 8 _{alkynyl, -OR 14, -O (CH 2} ) n OR 14, -C (O) R ₁₄ , —O—C (O) R _1
4 , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR
₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄
, —C (O) NHR ₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC
_{(O) R 14, -NHSR 14} , -NHSOR 14, -NHS (O) 2 R 14, -O (C
_{H 2) n C (O)} O (CH 2) n CH 3, O-C (S) R 14, O-C (S) OR 14,
_{O-C (S) NHR 14} , O-C (S) N (R 14) 2, -C (S) OR 14, -C (S
) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (S)
R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C (S
) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) ₂ , —NH (phenyl)
, —N (phenyl) ₂ , —NH (naphthyl), —N (naphthyl) ₂ , —CN, —NO ₂ ,
-N ₃ , -C ₁ -C ₈ alkyl, -O- (C ₁ -C ₈ alkyl),-(C ₁ -C ₈ alkyl) -OH, -C ₂ -C ₈ alkenyl, -C ₂ -C _{8 alkynyl,} -C 3 _{-C 12} cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _heterocycle, -OR _14, -O (CH _{2
) N OR 14, -C (O} ) R 14, -O-C (O) R 14, -C (O) (CH 2) n -R
₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄
) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR ₁₄ , —S—
R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —NHSR ₁₄ ,
—NHSOR ₁₄ , —NHS (O) ₂ R ₁₄ , O—C (S) R ₁₄ , O—C (S) OR _1
4 , O—C (S) NHR ₁₄ , O—C (S) N (R ₁₄ ) ₂ , —C (S) OR ₁₄ , —C
(S) NHR ₁₄ , —C (S) N (R ₁₄ ) ₂ , —NHC (S) R ₁₄ , —NR ₁₄ C (
S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ , —NR ₁₄ C
(S) NHR ₁₄ , —NR ₁₄ C (S) N (R ₁₄ ) ₂ ;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C _8. alkyl, -NH _(C 1 ~C _{5 alkyl), - N (C 1 ~C} 5 _alkyl) 2, -NH (phenyl), - N _(phenyl) 2, -
NH (naphthyl), —N (naphthyl) ₂ , —C (O) NH (C ₁ -C ₅ alkyl), —C
(O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC
(═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ ,
_{-O (CH 2) n OR 14} , -C (O) R 14, -O-C (O) R 14, -C (O) (C
H ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O
) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , —C (O) NHR
₁₄ , —S—R ₁₄ , —SOR ₁₄ , —S (O) ₂ R ₁₄ , —NHC (O) R ₁₄ , —N
_{HSR 14, -NHSOR 14, -NHS (} O) 2 R 14, O-C (S) R 14, O-C
(S) OR ₁₄ , OC (S) NHR ₁₄ , OC (S) N (R ₁₄ ) ₂ , —C (S) O
_{R 14, -C (S) NHR} 14, -C (S) N (R 14) 2, -NHC (S) R 14, -
NR ₁₄ C (S) R ₁₄ , —NHC (S) NHR ₁₄ , —NHC (S) N (R ₁₄ ) ₂ ,
_{-NR 14 C (S) NHR 14} , -NR 14 C (S) N (R 14) 2 and _either, together with _{R 11} and _{R 12,} 5-membered together with the carbon atom to which each is attached to 9 Forming a member heterocycle;
Each R ₁₄ is independently —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; Or
C ₂ -C ₈ alkynyl;
Y each independently, _-C 1 -C ₈ alkylene -, _- C 2 -C ₈ alkenylene - or _-C 2 -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]

In certain embodiments, —O-benzyl is unsubstituted.
In certain embodiments, R ₇ is 3-methoxybenzyloxy.
In certain embodiments, -phenyl is unsubstituted.

In certain embodiments, R ₁₄ is phenyldimethylamine. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is phenyldimethylamine.

In certain embodiments, R ₇ is —OCH ₂ C (O) OC ₂ H ₅ .
In certain embodiments, R ₁₄ is benzyloxyphenyl. In a more specific embodiment, R ₁ is C (O) NHR ₁₄ and R ₁₄ is benzyloxyphenyl.

In certain embodiments, R ₁₄ is para-bromophenyl. In a more specific embodiment, R ₁ is —C (O) R ₁₄ and R ₁₄ is para-bromophenyl.
In certain embodiments, R _a is para-hydroxyphenyl. In a more particular embodiment, _{Y m} is -CH ₂ - and _{and, R 14} is para - hydroxy phenyl.

In certain embodiments, R ₇ is —NH (phenyl) OCH ₃ .
In certain embodiments, R ₁ is — (CH ₂ ) ₂ OS (O) ₂ O ^— .
In certain embodiments, R ₁₁ and R ₁₂ are not joined together with the carbon atom to which each is attached.

In another aspect, the present invention provides a compound of formula (Ic) as defined above wherein Q ₂ and Q ₃ , R _{1 to} R ₈ and R _{10 to} R ₁₃ are as defined above for compounds of formula (Ic) A pharmaceutical composition comprising a compound of the formula:

In another aspect, the present invention provides a method for treating cancer in a patient, wherein the method provides a patient in need of treatment to the above formula (Ic) [wherein Q ₂ and Q ₃ , R _{1 to} R ₈ and R _{10 to} R ₁₃ are as defined above for compounds of formula (Ic)] or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a method for treating a virus or viral infection in a patient, wherein the method provides a patient in need of treatment to the above formula (Ic) [wherein Q ₂ and Q ₃ , R _{1 to} R ₈ and R _{10 to} R ₁₃ are as defined above for compounds of formula (Ic)] or a pharmaceutically acceptable salt thereof including.

3.1 Definitions and Abbreviations As used herein, “halogen” means —F, —Cl, —Br or —I.

As used herein, “C ₁ -C ₈ alkyl” refers to a straight or branched saturated hydrocarbon group containing from 1 to 8 carbon atoms, wherein the hydrocarbon group may be unsubstituted or substituted. it may, one or more - _{halogen, -NH 2, -OH, -O- (} C 1 ~C 8 alkyl), optionally substituted phenyl or naphthyl group. Examples of straight or branched C ₁ -C ₈ alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl 2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl- 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, 1- Examples include but are not limited to heptyl and 1-octyl.

As used herein, “C ₁ -C ₅ alkyl” refers to a straight or branched chain saturated hydrocarbon group containing 1 to 5 carbon atoms. Examples of linear or branched C ₁ -C ₅ alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl 2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,
Examples include, but are not limited to 2,2-dimethyl-1-propyl and 1-pentyl.

As used herein, “C ₂ -C ₈ alkenyl” refers to a straight or branched chain unsaturated hydrocarbon group containing 2 to 8 carbon atoms and at least one double bond, The hydrocarbon group may be unsubstituted or substituted with a phenyl group or a naphthyl group.

As used herein, “C ₂ -C ₈ alkynyl” refers to a straight or branched chain unsaturated hydrocarbon group containing 2 to 8 carbon atoms and at least one triple bond, The hydrocarbon group may be unsubstituted or substituted with a phenyl group or a naphthyl group.

As used herein, “C ₁ -C ₈ alkylene” refers to a C ₁ -C ₈ alkyl group in which one of the hydrogen atoms of the C ₁ -C ₈ alkyl group is replaced with a bond.
As used herein, “C ₂ -C ₈ alkenylene” refers to a C ₂ -C ₈ alkenyl group in which one of the hydrogen atoms of the C ₂ -C ₈ alkenyl group is replaced with a bond.

As used herein, “C ₂ -C ₈ alkynylene” refers to a C ₂ -C ₈ alkynyl group in which one of the hydrogen atoms of the C ₂ -C ₈ alkynyl group is replaced with a bond.
As used herein, “C ₃ -C ₁₂ cycloalkyl” refers to a monocyclic, bicyclic or tricyclic non-aromatic saturated cyclic hydrocarbon containing 3 to 12 carbon atoms. Point to. C ₃ ~C ₁
Examples of ₂ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, adamantyl, bicyclo [
2.2.2] oct-2-enyl and bicyclo [2.2.2] octyl,
These are not limited.

As used herein, a “-3 to 9-membered heterocycle” is a 3- to 9-membered single atom composed of carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. A cyclic or bicyclic aromatic ring or a non-aromatic ring. Examples of -3 to 9-membered heterocycles include aziridinyl, oxiranyl, thiylyl, azilinyl, diaziridinyl, diazilinyl, oxaziridinyl, azetidinyl, azetidinonyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, Triazinyl, tetrazinyl, imidazolyl, benzimidazolyl, tetrazolyl, indolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furanyl, pyridinyl, oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, Pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, isoin Including but Lil and indazolyl, but are not limited to.

A “5- to 9-membered ring” is a 5- to 9-membered monocyclic or bicyclic group consisting of only carbon atoms or consisting of carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. A cyclic aromatic ring or a non-aromatic ring. Examples of 5- to 9-membered rings include, but are not limited to, cyclopentyl, cyclohexyl or cycloheptyl, which are saturated or unsaturated, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, oxazinyl, thiazinyl, Diazinyl, triazinyl, tetrazinyl, imidazolyl, benzimidazolyl, tetrazolyl, indolyl, isoquinolinyl, quinolinyl, quinazolinyl, pyrrolidinyl, purinyl, isoxazolyl, benzisoxazolyl, furanyl, furazanyl, pyridinyl, oxazolyl, benzoxazolyl, thiazolyl, benzazolyl It may be thiophenyl, pyrazolyl, triazolyl, benzodiazolyl, benzotriazolyl, pyrimidinyl, isoindolyl and indazolyl.

As used herein, an -O-benzyl group can be substituted or unsubstituted.
As used herein, a -phenyl group may be substituted or unsubstituted.

When groups described herein are said to be “substituted or unsubstituted”, when substituted, these groups may adversely affect the desired activity of the compound. It may be optionally substituted with one or more desired substituents. Examples of preferred substituents are those described in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo or fluoro); C ₁ -C ₆ alkyl; C ₂ -C _{6 alkenyl;} C 2 -C ₆ alkynyl; _hydroxy; C 1 -C ₆ alkoxyl; amino; nitro; thiol; thioether; imine, cyano, amido, phosphonate, phosphine, carboxyl, thiocarbonyl, sulfonyl, sulfonamide; ketone An aldehyde; an ester; an oxygen (= O); a haloalkyl (eg, trifluoromethyl); a carbocyclic cycloalkyl (which may be monocyclic or fused or non-fused polycyclic, such as cyclopropyl,
Cyclobutyl, cyclopentyl or cyclohexyl), or heterocycloalkyl (
It may be monocyclic or fused or non-fused polycyclic, eg pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (eg , Phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiophenyl, benzothiophenyl, benzothiophenyl) ; benzyloxy; amino (primary, secondary or tertiary); - _{N (CH 3)} 2; O-lower alkyl; O-aryl, aryl; aryl - lower alkyl; CO CH _3; -OCH ₂ CH _{3; methoxy;} CONH _2; OCH 2
CONH _2; be _{OCF 3;; NH 2; SO} 2 NH 2; OCHF 2; CF 3 such components may, fused ring or bridge (e.g., -OCH ₂ O-) may be substituted by.

These substituents may be further substituted with a substituent selected from such a group.
“Effective amount” means to treat or prevent cancer or neoplastic disease; to inhibit the growth of cancer cells or neoplastic cells; to treat or prevent viral infections; Is the amount of the tricyclic heterocyclic compound effective to inhibit

As used herein with respect to a reaction mixture or organic solvent, the term “substantially anhydrous” means that the water the reaction mixture or organic solvent contains is less than about 1% by weight relative to the reaction mixture or organic solvent. In one embodiment, it means less than about 0.5 wt%, and in yet another embodiment, less than about 0.25 wt%.

In one embodiment, the tricyclic heterocyclic compound is administered in isolated form when administered to a patient, eg, to a mammal for veterinary use, or to a human for clinical use. As used herein, “isolated” means that the tricyclic heterocyclic compound is (a) a natural source such as a plant or cell, preferably a bacterial culture, or (b) synthetic. It means that the organic chemical reaction mixture is separated from components other than the tricyclic heterocyclic compound. In other embodiments, the tricyclic heterocyclic compound is purified via conventional techniques. As used herein, “purified” refers to a single at least 95%, preferably at least 98%, by weight of the isolate when the isolate is isolated. It means that a tricyclic heterocyclic compound is included.

As used herein, the term “T / C value” refers to (a) the change from baseline in the mean tumor volume of the treated mice, and the change from baseline in the mean tumor volume of the negative control mice. (B) A value obtained by multiplying the numerical value obtained in step (a) by 100.

The tricyclic heterocyclic compounds of the present invention can have one or more chiral centers and / or double bonds, and are therefore double bond isomers (ie, geometric isomers), enantiomers Or is understood to exist as a stereoisomer, such as a diastereoisomer. In the present invention, the chemical structures shown herein, and therefore the compounds of the present invention, all correspond to the enantiomers and stereoisomers, ie, sterically pure forms (eg, geometrically pure, (Enantiomerically pure or diastereomerically pure) and both enantiomeric and stereoisomeric mixtures, for example racemates.

As used herein, unless otherwise stated, the term “sterically pure”
It means a composition consisting of a compound of one type of stereoisomer and substantially free of other stereoisomers of the compound. For example, a sterically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A sterically pure composition of a compound having two chiral centers will be substantially free of other diastereoisomers of the compound. A typical sterically pure compound consists of more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer, more preferably one stereo of the compound. More than about 90% by weight of isomers and less than about 10% by weight of other stereoisomers, more preferably about 95% by weight of one stereoisomer of the compound.
More than about 5% by weight of super and other stereoisomers, particularly preferably one of the compounds
It consists of more than about 97% by weight of one type of stereoisomer and less than about 3% by weight of other stereoisomers.

Enantiomers of compounds of the present invention by well-known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of compounds as complexes of chiral salts or crystallization of compounds in chiral solvents. It is possible to separate the body mixture and the stereoisomer mixture into their individual enantiomers or stereoisomers. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

Note that if there is a discrepancy between the depicted structure and the name given to that structure, the depicted structure takes precedence. In addition, if the stereochemistry of a structure or part of a structure is not shown, for example, with a bold or dotted line, it is understood that the structure or part of the structure encompasses all stereoisomers thereof. I want.

Unless otherwise stated, the following abbreviations and their definitions are used herein.

[Abbreviation] [Definition]
_{BOC -C (O) OC (CH} 3) 3
DEF N, N-diethylformamide dppf 1,1-bis (diphenylphosphino) ferrocene DMF N, N-dimethylformamide DMSO dimethylsulfoxide THF tetrahydrofuran EtOAc ethyl acetate EtOH ethanol MeOH methanol Tf-SO ₂ CF ₃
dba dibenzylideneacetone Ph phenyl TBDMSCl t-butyldimethylsilyl chloride DBU 1,8-diazabicyclo [5.4.0] undec-7-ene LC / MS liquid chromatography / mass spectrometry

5. Detailed Description of the Invention 5.1 Tricyclic Heterocyclic Compounds of Formula (Ia) As noted above, the present invention provides compounds of formula (Ia):

And a pharmaceutically acceptable salt thereof, wherein Q _{1 to} Q ₄ , R ₂ ,
R ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are as defined above for compounds of formula (Ia)].

A first subclass of tricyclic heterocyclic compounds of formula (Ia)
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A second subclass of tricyclic heterocyclic compounds of formula (Ia) is
Q ₁ is —O—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A third subclass of tricyclic heterocyclic compounds of formula (Ia) is
Q ₁ is -S-;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A fourth subclass of tricyclic heterocyclic compounds of formula (Ia) is
Q ₁ is —NH—;
Q ₂ is —N—;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A fifth subclass of tricyclic heterocyclic compounds of formula (Ia)
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —N—;
Q ₄ is —C (R ₉ ) —.

A sixth subclass of tricyclic heterocyclic compounds of formula (Ia)
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —CH—.
R ₂ and R ₆ are —H.

A seventh subclass of tricyclic heterocyclic compounds of formula (Ia)
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —CH—.
_{R 2, R 4, R 6} , R 8 and _R 10 _{to R 13} is -H.

An eighth subclass of the tricyclic heterocyclic compound of formula (Ia) is
Q ₁ is —NH—;
Q ₂ is —C (C ₁ -C ₈ alkyl)-;
Q ₃ is —C (C ₁ -C ₈ alkyl)-;
Q ₄ is —CH—.
_{R 2, R 4, R 6} , R 8 and _R 10 _{to R 13} is an -H;
R ₇ is —O— (C ₁ -C ₈ alkyl)-.

  Examples of tricyclic heterocyclic compounds of formula (Ia) are:

Or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutically acceptable salt of Compound 1 is a tartrate salt. In other embodiments, the pharmaceutically acceptable salt of Compound 1 is a mesylate salt.

  Other examples of tricyclic heterocyclic compounds of formula (Ia) are shown below:

As well as their pharmaceutically acceptable salts.
5.2 Tricyclic heterocyclic compounds of formula (Ib) As mentioned above, the present invention provides compounds of formula (Ia):

[Wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ are defined above for the compound of formula (Ib)]
And pharmaceutically acceptable salts thereof.

The present invention further provides a composition comprising a pharmaceutically acceptable carrier and an effective amount of a tricyclic heterocyclic compound of formula (Ib) or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing cancer or neoplastic disease, wherein the method provides a patient in need of such treatment or prevention with an effective amount of formula (Ia) or (Ib)
And administering a tricyclic heterocyclic compound.

The present invention further provides a method of inhibiting the growth of cancer cells or neoplastic cells, wherein the method comprises a cancer cell or neoplastic cell and an effective amount of a tricyclic complex of formula (Ia) or (Ib). Contacting with a ring compound.

The present invention further provides a method of treating or preventing viral infection, wherein the method provides an effective amount of a tricyclic heterocyclic compound of formula (Ia or Ib) to a patient in need of such treatment or prevention. Administration.

The present invention further provides a method of inhibiting viral replication or infectivity, comprising:
Contacting the virus or virus-infected cell with an effective amount of a tricyclic heterocyclic compound of formula (Ia) or (Ib).

The first subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A second subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is —O—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A third subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is -S-;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A fourth subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is —NH—;
Q ₂ is —N—;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —C (R ₉ ) —.

A fifth subclass of tricyclic heterocyclic compounds of formula (Ib) is
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —N—;
Q ₄ is —C (R ₉ ) —.

A sixth subclass of tricyclic heterocyclic compounds of formula (Ib)
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —CH—.
R ₂ and R ₆ are —H.

A seventh subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is —NH—;
Q ₂ is —C (R ₃ ) —;
Q ₃ is —C (R ₅ ) —;
Q ₄ is —CH—.
_{R 2, R 4, R 6} , R 8 and _R 10 _{to R 13} is -H.

The eighth subclass of the tricyclic heterocyclic compound of formula (Ib) is
Q ₁ is —NH—;
Q ₂ is —C (C ₁ -C ₈ alkyl)-;
Q ₃ is —C (C ₁ -C ₈ alkyl)-;
Q ₄ is —CH—.
_{R 2, R 4, R 6} , R 8 and _R 10 _{to R 13} is an -H;
R ₇ is —O— (C ₁ -C ₈ alkyl).

In one embodiment, the present invention provides a composition comprising a pharmaceutically acceptable carrier and Compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutically acceptable salt is tartrate. In yet other embodiments, the pharmaceutically acceptable salt is mesylate.

In another embodiment, the compound that can be used in the present method is Compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutically acceptable salt is tartrate. In yet other embodiments, the pharmaceutically acceptable salt is mesylate.

5.3 Tricyclic Heterocyclic Compounds of Formula II As noted above, the present invention provides compounds of formula (II):

And a pharmaceutically acceptable salt thereof, wherein Q ₁ , Q ₄ , R
₆ to R ₈ and _R 10 _{to R 13} are defined above for the compounds of formula (II)]
.

The first subclass of the tricyclic heterocyclic compound of formula (II) is
Q ₁ is —NH—;
Q ₄ is —C (R ₉ ) —.

A second subclass of the tricyclic heterocyclic compound of formula (II) is
Q ₁ is —O—;
Q ₄ is —C (R ₉ ) —.

A third subclass of the tricyclic heterocyclic compound of formula (II) is
Q ₁ is -S-;
Q ₄ is —C (R ₉ ) —.

A fourth subclass of tricyclic heterocyclic compounds of formula (II) is
Q ₁ is —NH—;
Q ₄ is —CH—.
R ₆ is —H.

A fifth subclass of tricyclic heterocyclic compounds of formula (II) is
Q ₁ is —NH—;
Q ₄ is —CH—.
R ₆ is —H;
R _{10 to} R ₁₃ are —H.

A sixth subclass of the tricyclic heterocyclic compound of formula (II) is
Q ₁ is —NH—;
Q ₄ is —CH—.
R ₆ is —H;
R ₈ and R _{10 to} R ₁₃ are —H;
R ₇ is —O— (C ₁ -C ₈ alkyl).

The present invention further provides a composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of treating or preventing cancer or neoplastic disease, wherein the method provides a patient in need of such treatment or prevention with an effective amount of a tricyclic complex of formula (II). Comprising administering a ring compound.

The present invention further provides a method of inhibiting the growth of cancer cells or neoplastic cells, wherein the method comprises combining a cancer cell or neoplastic cell with an effective amount of a tricyclic heterocyclic compound of formula (II). Consisting of contact.

The present invention further provides a method of treating or preventing viral infection, wherein the method administers an effective amount of a tricyclic heterocyclic compound of formula (II) to a patient in need of such treatment or prevention. Made up of.

The present invention further provides a method of inhibiting viral replication or infectivity, comprising:
Contacting the virus or virus-infected cell with an effective amount of a tricyclic heterocyclic compound of formula (II).

5.4 Methods for Preparing Tricyclic Heterocyclic Compounds The present invention further provides methods that can be used to prepare tricyclic heterocyclic compounds.
The compounds of the present invention can be obtained by conventional, well-known synthetic methods. For example,
March, J., “Advanced Organic Chem.
ilustry; Reactions Mechanisms, and Structure
"See 4th edition, 1992." An example of the method is described below. Starting materials that can be used to prepare the compounds of the invention and intermediates therefor are either commercially available or can be prepared from commercially available materials using well-known synthetic methods and reagents.

An example of a synthetic route that can be used to prepare tricyclic heterocyclic compounds is shown in Scheme 1 below and generalized.
The tricyclic heterocyclic compound can be obtained by, for example, conventional organic synthesis as shown below. Scheme 1 shows a general method by which tricyclic heterocyclic compounds can be obtained,
Q _{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ in Scheme 1 are represented by the formula (
The tricyclic heterocyclic compounds of Ia), (Ib) and (II) are defined above.

For example, commercially available or synthetically prepared pyrrolidinones of formula (i) are subjected to Vilsmeier formylation in the presence of phosphoryl bromide and alkylformamide to produce brominated pyrrolylaldehydes or brominations of formula (ii) Pyrrolyl enamine (i
ia) is obtained. Next, a compound of formula (ii) or (iii) and a boronic acid of formula (iii) are subjected to a cross-coupling reaction with a palladium or nickel catalyst to produce a compound of formula (II
) Is obtained. The compound of formula (II) is then converted to formula (iv) under acidic conditions.
) To give a compound of formula (Ia) or (Ib). In another embodiment, the compound of formula (II) is replaced with a compound of formula (v) (anion of a compound of formula (iv))
To give a compound of formula (Ia) or (Ib).

5.4.1 Preparation of Compound of Formula (Ia) from Compound of Formula (II) by Acid-Mediated Coupling In one particular embodiment, the present invention provides a tricyclic heterocyclic compound of formula (Ia) :

In the presence of an organic solvent and a protonic acid.
A compound of formula (II) for a time and temperature sufficient to prepare a compound of:

And a compound of formula (iv):

Wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ are as defined above for the tricyclic heterocyclic compound of formula (Ia) Defined].

Thin layer chromatography (“TLC”), high performance liquid chromatography (“HPLC”)
), Gas chromatography (“GC”), and conventional analytical techniques including (but not limited to) nuclear magnetic resonance spectroscopy (“NMR”) such as ¹ H or ¹³ C NMR. ) Formation of tricyclic heterocyclic compounds can be monitored.

The concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture is usually in the range of about 0.01 mol to about 3 mol per liter of reaction mixture. In one embodiment, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.05 mole to about 1 mole per liter of reaction mixture. In other embodiments, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.1 mole to about 0.5 mole per liter of reaction mixture.

The amount of compound of formula (iv) in the reaction mixture is usually in an excess of at least about 1.5 times molar to about 10 times molar relative to the amount of tricyclic heterocyclic compound of formula (II). Exists. In one embodiment, the amount of the compound of formula (iv) in the reaction mixture is at least about 2 fold molar to about 10 fold molar excess relative to the amount of tricyclic heterocyclic compound of formula (II). Present in quantity. In other embodiments, the amount of compound of formula (iv) in the reaction mixture is at least about 3 fold molar to about 10 fold molar relative to the amount of tricyclic heterocyclic compound of formula (II). Present in excess.

The amount of protonic acid in the reaction mixture is usually in the range of about 0.0001 to about 5 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the amount of protic acid in the reaction mixture ranges from about 0.001 to about 3 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the amount of protonic acid in the reaction mixture is of the formula (II)
In the range of about 0.01 to about 1 molar equivalent per equivalent of the tricyclic heterocyclic compound.

Protic acids suitable for use in the method of the present invention include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, perchloric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid. Include, but are not limited to, romethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, p-trifluoromethylbenzenesulfonic acid, mixtures thereof and aqueous mixtures. Not done.
In one embodiment, the protic acid is an aqueous hydrochloric acid solution or an aqueous hydrobromic acid solution.

The reaction mixture further includes an organic solvent. Suitable organic solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol and t-butanol; ethers such as diethyl ether, diisopropyl ether, THF and dioxane. In one embodiment, the solvent is methanol or ethanol.

In one embodiment, the reaction mixture is substantially anhydrous.
The amount of organic solvent in the reaction mixture is usually present in an amount of at least about 10 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount of at least about 20 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount of at least about 30 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is
Present in the reaction mixture in an amount of at least about 40 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount ranging from about 10 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 20 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments,
The organic solvent is about 30 molar equivalents to about 100 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II).
Present in the reaction mixture in an amount in the range of 0 molar equivalents. In other embodiments, the organic solvent is of the formula (
II) is present in the reaction mixture in an amount ranging from about 40 molar equivalents to about 1000 molar equivalents per equivalent of tricyclic heterocyclic compound.

Usually, the reaction proceeds over a time period ranging from about 5 minutes to about 20 hours. In one embodiment, the reaction proceeds over a time period ranging from about 10 minutes to about 10 hours. In other embodiments, the reaction proceeds over a time period ranging from about 30 minutes to about 2 hours.

Usually, the reaction temperature ranges from about 25 ° C to about 100 ° C. In one embodiment, the reaction temperature ranges from about 25 ° C to about 40 ° C. In other embodiments, the reaction temperature is about room temperature.

Usually, the overall yield of the tricyclic heterocyclic compound of the formula (Ia) to be isolated and purified is based on the amount of the tricyclic heterocyclic compound of the formula (II) or the amount of the compound of the formula (iv). Over about 70 percent. In one embodiment, the overall yield of the isolated tricyclic heterocyclic compound of formula (Ia) is equal to the amount of tricyclic heterocyclic compound of formula (II) or the amount of compound of formula (iv). On the other hand, it exceeds about 75%. In other embodiments, the overall yield of the isolated tricyclic heterocyclic compound of formula (Ia) is the amount of tricyclic heterocyclic compound of formula (II) or tricyclic of formula (iv) More than about 80 percent based on the amount of heterocyclic compound.

5.4.2 Method of preparing a compound of formula (Ia) from a compound of formula (II) via a condensation reaction In another embodiment, the present invention provides a method of preparing a compound of formula (Ia) This way:
(A) Formula (II) in the presence of a substantially anhydrous aprotic organic solvent:

  A compound of formula (v):

[Wherein M is Li, Na, K, Rb or Cs]
A compound of formula (vi):

[Wherein M is defined as above]
Contacting for a time and at a temperature sufficient to prepare a compound of:
(B) protonating the compound of formula (vi) with an H ⁺ donor at a time and temperature sufficient to prepare a compound of formula (Ia), wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are as defined above for compounds of formula (Ia)].

Monitoring the formation of the tricyclic heterocyclic compound of formula (Ia) using conventional analytical techniques including but not limited to TLC, HPLC, GC and NMR such as ¹ H or ¹³ C NMR Is possible.

The concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture is usually in the range of about 0.01 mol to about 3 mol per liter of reaction mixture. In one embodiment, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.05 mole to about 1 mole per liter of reaction mixture. In other embodiments, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.1 mole to about 0.5 mole per liter of reaction mixture.

The amount of the compound of formula (v) in the reaction mixture is usually an excess of about 1 equivalent to about 2 times molar concentration with respect to 1 equivalent of the tricyclic heterocyclic compound of formula (II). In one embodiment, the amount of compound of formula (v) in the reaction mixture is approximately equimolar with respect to the amount of tricyclic heterocyclic compound of formula (II).

In one embodiment, the reaction mixture is substantially anhydrous.
Using methods well known to those skilled in the field of organic synthesis, the compound of formula (iv)
The compound of formula (v) can be prepared by deprotonation with a base such as n-butyllithium. For examples of methods that can be used to prepare compounds of formula (v) from compounds of formula (iv) using a base, see Martinez et a
l. ), J.M. Org. Chem. 46, 3760 (1981) and Minato et al. (Mi)
nato et al. ), Tetrahedron Lett. , 22: 5319 (1
981).

The reaction mixture further comprises a substantially anhydrous aprotic organic solvent. Suitable aprotic solvents include, but are not limited to, THF, DMF, DMSO, N-methylpyrrolidinone and diethyl ether. Such aprotic solvents can be made substantially anhydrous by storing on a desiccant, storing on a molecular sieve, or by distillation.

In one embodiment, the aprotic solvent is substantially anhydrous THF distilled from sodium benzophenone ketyl.
The amount of organic solvent in the reaction mixture is usually at least about 10 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount of at least about 20 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount of at least about 30 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is of the formula (II
) In the reaction mixture in an amount of at least about 40 molar equivalents per equivalent of tricyclic heterocyclic compound. In one embodiment, the organic solvent is present in the reaction mixture in an amount ranging from about 10 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 20 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 30 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 40 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II).

Usually, step (a) is carried out at a temperature of about -78 ° C to about 100 ° C. In one embodiment, step (a) is performed at a temperature of about −25 ° C. to about 75 ° C. In other embodiments, step (a) is carried out at a temperature from about −10 ° C. to about 30 ° C. Usually, step (a) is carried out for a sufficient time such that a reaction mixture is obtained in which the tricyclic heterocyclic compound of formula (II) is reduced by at least about 85 percent relative to the original amount. In one embodiment, step (a) is carried out for a sufficient amount of time such that a reaction mixture is obtained in which the tricyclic heterocyclic compound of formula (II) is reduced by at least about 90 percent relative to the original amount. In other embodiments, step (a) is carried out for a sufficient amount of time such that a reaction mixture is obtained in which the tricyclic heterocyclic compound of formula (II) is reduced by at least about 93 percent relative to the original amount. The progress of the reaction can be monitored using conventional analytical techniques such as, but not limited to, the methods described above.

Usually, step (a) is carried out over a period in the range of about 0.5 hours to about 48 hours. 1
In embodiments, step (a) is performed over a period of time ranging from about 2 hours to about 24 hours.
In other embodiments, step (a) is performed over a period of time ranging from about 4 hours to 12 hours.

The reaction of the present invention further comprises the step of protonating the compound of formula (vi) with an H ⁺ donor.
Suitable H ⁺ donors include, but are not limited to, water and protic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, perchloric acid, nitric acid, methanesulfonic acid, Ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, p-trifluoromethylbenzenesulfonic acid, and mixtures thereof are included. In one embodiment, the acid is hydrochloric acid or hydrobromic acid. In other embodiments, the acid is an aqueous hydrochloric acid solution or an aqueous hydrobromic acid solution.

Usually, step (b) is carried out over a period ranging from about 10 seconds to about 1 hour. In one embodiment, step (b) is performed over a period of time ranging from about 30 seconds to about 0.5 hours. In other embodiments, step (b) is performed over a period of time ranging from about 1 minute to about 10 minutes.

Compounds of formula (Ia) can be isolated and purified as described above.
5.4.3 Preparation of Compound of Formula (Ib) from Compound of Formula (II) by Acid-Mediated Coupling In one particular embodiment, the present invention provides compound of formula (Ib):

Of the formula (IIb) in the presence of an organic solvent and a protonic acid for a time and at a temperature sufficient to prepare the compound of formula (Ib). ) Compound:

And formula (iv):

[Wherein Q _{1 to} Q ₄ , R ₂ , R ₄ , R _{6 to} R ₈ and R _{10 to} R ₁₃ represent a tricyclic heterocyclic compound of the formula (Ib)] As defined above].

Thin layer chromatography (“TLC”), high performance liquid chromatography (“HPLC”)
), Gas chromatography (“GC”), and conventional analytical techniques including (but not limited to) nuclear magnetic resonance spectroscopy (“NMR”) such as ¹ H or ¹³ C NMR. ) Formation of tricyclic heterocyclic compounds can be monitored.

The concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture is usually in the range of about 0.01 mol to about 3 mol per liter of reaction mixture. In one embodiment, the formula (
The concentration of the tricyclic heterocyclic compound of II) ranges from about 0.05 mol to about 1 mol per liter of reaction mixture. In other embodiments, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.1 mole to about 0.5 mole per liter of reaction mixture.

The amount of compound of formula (iv) in the reaction mixture is usually at least about 1.5-fold molar excess to about 10-fold molar excess relative to the amount of tricyclic heterocyclic compound of formula (II). Present in quantity. In one embodiment, the amount of compound of formula (iv) in the reaction mixture is at least about 2-fold molar excess to about 10-fold molar concentration relative to the amount of tricyclic heterocyclic compound of formula (II). Present in excess. In other embodiments, the amount of compound of formula (iv) in the reaction mixture is at least about 3 times molar excess to about 10 times mol relative to the amount of tricyclic heterocyclic compound of formula (II). Present in excess of concentration.

The amount of protonic acid in the reaction mixture is usually in the range of about 0.0001 to about 5 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the amount of protic acid in the reaction mixture ranges from about 0.001 to about 3 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the amount of protonic acid in the reaction mixture is of the formula (II)
In the range of about 0.01 to about 1 molar equivalent per equivalent of the tricyclic heterocyclic compound.

Protic acids suitable for use in the method of the present invention include hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, perchloric acid, nitric acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid. Include, but are not limited to, romethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, p-trifluoromethylbenzenesulfonic acid, mixtures thereof and aqueous mixtures. Not done.
In one embodiment, the protic acid is an aqueous hydrochloric acid solution or an aqueous hydrobromic acid solution.

The reaction mixture further includes an organic solvent. Suitable organic solvents include, but are not limited to, alcohols such as methanol, ethanol, isopropanol and t-butanol; ethers such as diethyl ether, diisopropyl ether, THF and dioxane. In one embodiment, the solvent is methanol or ethanol.

In one embodiment, the reaction mixture is substantially anhydrous.
The amount of organic solvent in the reaction mixture is usually present in an amount of at least about 10 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount of at least about 20 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount of at least about 30 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is
Present in the reaction mixture in an amount of at least about 40 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount ranging from about 10 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 20 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 30 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In another embodiment, the organic solvent is of formula (II)
Present in the reaction mixture in an amount ranging from about 40 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound.

Usually, the reaction proceeds over a time period ranging from about 5 minutes to about 20 hours. In one embodiment, the reaction proceeds over a time period ranging from about 10 minutes to about 10 hours. In other embodiments,
The reaction proceeds over a time period ranging from about 30 minutes to about 2 hours.

Usually, the reaction temperature ranges from about 25 ° C to about 100 ° C. In one embodiment, the reaction temperature ranges from about 25 ° C to about 40 ° C. In other embodiments, the reaction temperature is about room temperature.
Usually, the overall yield of the isolated and purified tricyclic heterocyclic compound of the formula (Ib) is based on the amount of the tricyclic heterocyclic compound of the formula (II) or the amount of the compound of the formula (iv). Over about 70 percent. In one embodiment, the overall yield of isolated and purified tricyclic heterocyclic compound of formula (Ib) is equal to the amount of tricyclic heterocyclic compound of formula (II) or the amount of compound of formula (iv). On the other hand, it exceeds about 75%. In other embodiments, the overall yield of isolated and purified tricyclic heterocyclic compound of formula (Ib) is the amount of tricyclic heterocyclic compound of formula (II) or the amount of compound of formula (iv). In contrast, it exceeds about 80 percent.

5.4.4 Method of preparing a compound of formula (Ib) from a compound of formula (II) via a condensation reaction In another embodiment, the present invention provides a method of preparing a compound of formula (Ib) This way:
(A) Formula (II) in the presence of a substantially anhydrous aprotic organic solvent:

A compound of formula (v):

[Wherein M is Li, Na, K, Rb or Cs]
A compound of formula (vi):

[Wherein M is defined as above]
Contacting for a time and at a temperature sufficient to prepare
(B) protonating the compound of formula (vi) with an H ⁺ donor at a time and temperature sufficient to prepare the compound of formula (Ib), wherein Q ₁ -Q ₄ , R ₂ , R ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are as defined above for compounds of formula (Ib)].

Monitoring the formation of tricyclic heterocyclic compounds of formula (Ib) using conventional analytical techniques including, but not limited to, TLC, HPLC, GC and NMR such as ¹ H or ¹³ C NMR Is possible.

The concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture is usually in the range of about 0.01 mol to about 3 mol per liter of reaction mixture. In one embodiment, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture is from about 0.05 moles per liter of reaction mixture.
The range is about 1 mole. In other embodiments, the concentration of the tricyclic heterocyclic compound of formula (II) in the reaction mixture ranges from about 0.1 mole to about 0.5 mole per liter of reaction mixture.

The amount of compound of formula (v) in the reaction mixture is usually an excess of about 1 molar equivalent to about 2 molar concentrations relative to the amount of tricyclic heterocyclic compound of formula (II). In one embodiment, the amount of compound of formula (v) in the reaction mixture is about 1 molar equivalent relative to the amount of tricyclic heterocyclic compound of formula (II).

In one embodiment, the reaction mixture is substantially anhydrous.
Using methods well known to those skilled in the field of organic synthesis, the compound of formula (iv)
The compound of formula (v) can be prepared by deprotonation with a base such as n-butyllithium. For examples of methods that can be used to prepare compounds of formula (v) from compounds of formula (iv) using a base, see Martinez et a
l. ), J.M. Org. Chem. 46, 3760 (1981) and Minato et al. (Mi)
nato et al. ), Tetrahedron Lett. , 22: 5319 (1
981).

The reaction mixture further comprises a substantially anhydrous aprotic organic solvent. Suitable aprotic solvents include, but are not limited to, THF, DMF, DMSO, N-methylpyrrolidinone and diethyl ether. Such aprotic solvents can be rendered substantially anhydrous by storage on a desiccant, on a molecular sieve, or by distillation.

In one embodiment, the aprotic solvent is substantially anhydrous THF distilled from sodium benzophenone ketyl.
The amount of organic solvent in the reaction mixture is usually at least about 10 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In one embodiment, the organic solvent is present in the reaction mixture in an amount of at least about 20 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount of at least about 30 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is of the formula (II
) In the reaction mixture in an amount of at least about 40 molar equivalents per equivalent of tricyclic heterocyclic compound. In one embodiment, the organic solvent is present in the reaction mixture in an amount ranging from about 10 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II). In another embodiment, the organic solvent is from about 20 molar equivalents to about 1 per equivalent of tricyclic heterocyclic compound of formula (II).
Present in the reaction mixture in an amount in the range of 000 molar equivalents. In other embodiments, the organic solvent is
Present in the reaction mixture in an amount ranging from about 30 molar equivalents to about 1000 molar equivalents per equivalent of tricyclic heterocyclic compound of formula (II). In other embodiments, the organic solvent is present in the reaction mixture in an amount ranging from about 40 molar equivalents to about 1000 molar equivalents per equivalent of the tricyclic heterocyclic compound of formula (II).

Usually, step (a) is carried out at a temperature of about -78 ° C to about 100 ° C. In one embodiment, step (a) is performed at a temperature of about −25 ° C. to about 75 ° C. In other embodiments, step (a) is carried out at a temperature from about −10 ° C. to about 30 ° C. Usually, step (a) is carried out for a sufficient time such that a reaction mixture is obtained in which the amount of the tricyclic heterocyclic compound of formula (II) is reduced by at least about 85 percent relative to the original amount. In one embodiment, it is carried out for a sufficient amount of time such that a reaction mixture is obtained in which the amount of the tricyclic heterocyclic compound of formula (II) is reduced by at least about 90 percent relative to the original amount. In other embodiments, it is carried out for a sufficient amount of time such that a reaction mixture is obtained in which the amount of the tricyclic heterocyclic compound of formula (II) is reduced by at least about 93 percent relative to the original amount. The progress of the reaction can be monitored using conventional analytical techniques including, but not limited to, any of the methods described above.

Usually, step (a) is carried out over a period in the range of about 0.5 hours to about 48 hours. 1
In embodiments, step (a) is performed over a period of time ranging from about 2 hours to about 24 hours.
In other embodiments, step (a) is performed over a period of time ranging from about 4 hours to 12 hours.

The reaction further comprises protonating the compound of formula (vi) with an H ⁺ donor.
Suitable H ⁺ donors include, but are not limited to, water as well as protic acids such as hydrochloric acid,
Hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, perchloric acid, nitric acid, methanesulfonic acid,
Ethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, p-trifluoromethylbenzenesulfonic acid, and mixtures thereof are included. In one embodiment, the acid is hydrochloric acid or hydrobromic acid. In other embodiments, the acid is an aqueous hydrochloric acid solution or an aqueous hydrobromic acid solution.

Usually step (b) is carried out over a time period ranging from about 10 seconds to about 1 hour. In one embodiment, step (b) is performed over a time period ranging from about 30 seconds to about 0.5 hours. In other embodiments, step (b) is performed for a time ranging from about 1 minute to about 10 minutes.

Compounds of formula (Ib) can be isolated and purified as described above.
5.4.5 Methods for Preparing Compounds of Formula (II) Using Boronic Acid In another embodiment, the present invention provides compounds of formula (II):

The method comprises preparing an organic solvent, a base and a Ni catalyst or Pd
In the presence of a catalyst at a time and temperature sufficient to prepare a compound of formula (II)
Or a compound of formula (ia)

And a compound of formula (iii):

Wherein Q ₁ , Q ₄ , R ₆ -R ₈ and R ₁₀ -R ₁₃ are as defined above for compounds of formula (II), and R ₁₅ is independently C _{1 to} C ₈ alkyl, cycloalkyl or phenyl].

Monitoring the formation of tricyclic heterocyclic compounds of formula (II) using conventional analytical techniques including but not limited to NMR, such as TLC, HPLC, GC and ¹ H or ¹³ C NMR. Is possible.

The concentration of the compound of formula (ii) or (ia) is usually about 0.01 per liter of solvent.
The range is from mole to about 3 moles. In one embodiment, the concentration of the compound of formula (ii) or (ia) ranges from about 0.05 mole to about 1 mole per liter of solvent. In other embodiments, the concentration of the compound of formula (ii) or (ia) ranges from about 0.1 mole to about 0.5 mole per liter of solvent.

The amount of compound of formula (iii) is usually in the range of about 1 molar equivalent to about 3 times molar excess per equivalent of compound of formula (ii) or (ia). In one embodiment, the amount of the compound of formula (iii) ranges from about 1 molar equivalent to about 2-fold molar excess per equivalent of compound of formula (ii) or (iii). In other embodiments, the amount of compound of formula (iii) is selected from formula (iii)
An excess of about 1.5 fold molarity per equivalent of compound of ii) or (iii).

Suitable bases for use in this method include, but are not limited to, alkali metal carbonates such as Na ₂ CO ₃ and K ₂ CO ₃ ; LiOH, NaOH, KOH, RbOH, Cs
OH, FrOH, Be (OH) ₂ , Mg (OH) ₂ , Ca (OH) ₂ , Sr (OH) ₂ ,
Alkaline earth and alkaline earth metal hydroxides such as Ba (OH) ₂ and Ra (OH) ₂ ; and LiOR, NaOR, KOR, RbOR, CsOR, FrOR, Be (OR
) ₂ , Mg (OR) ₂ , Ca (OR) ₂ , Sr (OR) ₂ , Ba (OR) ₂ and Ra (
OR) ₂ (wherein R is an alkyl group such as, but not limited to, methyl, ethyl, n-butyl, t-butyl or iso-propyl) and alkaline earth metal alkoxides Is included. Other bases suitable for use in this method include sodium acetate, potassium acetate, K ₃ PO ₄ , TlOH and hindered amines such as triethylamine and diisopropylethylamine. In one embodiment, the base is
Ba (OH) ₂ .

The amount of base is usually an excess of about 1 molar equivalent to about 3 molar concentrations per equivalent of compound of formula (ii) or (ia). In one embodiment, the amount of base is selected from formula (ii) or (iii)
) In excess of about 1 molar equivalent to about 2 molar concentrations per equivalent of compound. In other embodiments, the amount of base is an excess of about 1.5 fold molarity per equivalent of compound of formula (ii) or (iii). In other embodiments, the amount of base and the amount of compound of formula (iii) are equimolar.

Ni and Pd catalysts suitable for use in the present invention include, but are not limited to, Pd
(Dppf) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dba) ₂ (PPh ₃ ) ₂ , Pd (
PPh ₃ ) ₂ Cl ₂ , Pd (dba) ₂ , Pd ₂ (dba) ₃ / P (OMe) ₃ , Pd ₂
(Dba) ₃ / P (t-butyl) ₃ , NiCl ₂ [P (OMe) ₃ ] ₂ , Ni (dppf
) ₂ Cl ₂ , Ni (NEt ₂ ) ₂ Cl ₂ and Ni (PPh ₃ ) ₄ . In one embodiment, the catalyst is Pd (dppf) ₂ Cl ₂ .

The amount of Ni or Pd catalyst usually ranges from about 0.001 molar equivalents to about equimolar amounts per equivalent of compound of formula (ii) or (ia). In one embodiment, the amount of catalyst typically ranges from about 0.01 molar equivalents to about 0.5 molar equivalents per equivalent of compound of formula (ii) or (ia). In other embodiments, the amount of catalyst typically ranges from about 0.05 molar equivalents to about 0.2 molar equivalents per equivalent of compound of formula (ii) or (ia).

The amount of organic solvent is usually at least about 10 molar equivalents per equivalent of compound of formula (ii) or (ia). In one embodiment, the organic solvent is present in an amount of at least about 20 molar equivalents per equivalent of compound of formula (ii) or (ia). In other embodiments, the organic solvent is present in an amount of at least about 30 molar equivalents per equivalent of compound of formula (ii) or (iii). In other embodiments, the organic solvent is present in an amount of at least about 40 molar equivalents per equivalent of compound of formula (ii) or (ia). In one embodiment, the organic solvent has the formula (i
present in an amount ranging from about 10 molar equivalents to about 1000 molar equivalents per equivalent of compound of i) or (ia). In other embodiments, the organic solvent is present in an amount ranging from about 20 molar equivalents to about 1000 molar equivalents per equivalent of compound of formula (ii) or (iii). In another embodiment, the organic solvent is from about 30 molar equivalents per equivalent of compound of formula (ii) or (iii)
Present in an amount ranging from about 1000 molar equivalents. In another embodiment, the organic solvent is of formula (ii)
Or present in the reaction mixture in an amount ranging from about 40 molar equivalents to about 1000 molar equivalents per equivalent of compound of (ia).

Usually, the time ranges from about 1 hour to about 20 hours. In one embodiment, the time ranges from about 1 hour to about 10 hours. In other embodiments, the time ranges from about 2 hours to 6 hours.

Usually, the temperature ranges from about 25 ° C to about 150 ° C. In other embodiments, the temperature is about 4
It is in the range of 0 ° C to about 120 ° C. In other embodiments, the temperature is from about 50 ° C to about 100 ° C.

Suitable solvents include, but are not limited to ethers such as diethyl ether and diisopropyl ether; THF, dioxane, DMF, DMF / water, DMSO, benzene and toluene.

In one embodiment, the solvent is a DMF / water mixture.
In one particular embodiment, the solvent is a 4: 1 DMF / water mixture.
Compounds of formula (II) can be isolated and purified as described above for tricyclic heterocyclic compounds of formula (Ib).

5.5 Therapeutic / Prophylactic Administration and Composition Because of its activity, the tricyclic heterocyclic compounds of the present invention are advantageously useful in veterinary or human medicine. For example, the tricyclic heterocyclic compounds of the present invention are useful for the treatment or prevention of cancer or neoplastic disease or to inhibit the growth of cancer cells or neoplastic cells.
The tricyclic heterocyclic compounds of the present invention are also useful for the treatment or prevention of viral infections or to inhibit viral replication or infectivity.

The present invention provides methods of treatment and prevention by administering an effective amount of a tricyclic heterocyclic compound to a patient. The patient is a human, mammal, or non-human animal, such as an animal such as a cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig, more preferably Is a mammal, most preferably a human.

A composition of the invention comprising an effective amount of a tricyclic heterocyclic compound can be administered by any convenient route, for example by injection or bolus injection, epithelial or mucosal lining (eg, oral mucosa, rectal mucosa, and intestinal mucosa). Etc.) and can be administered with another biologically active agent. Systemic administration or local administration may be used. Encapsulation in various delivery systems such as liposomes, microparticles, microcapsules, capsules, etc. is known and can be used to administer tricyclic heterocyclic compounds. In certain embodiments, a plurality of tricyclic heterocyclic compounds are administered to the patient. Methods of administration include, but are not limited to: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,
Intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical to the ear, nose, eyes, or skin Administration.
The preferred mode of administration is at the discretion of the practitioner and will depend in part on the site of the disease (eg, the site of cancer or viral infection).

In certain embodiments, it may be desirable to administer one or more tricyclic heterocyclic compounds locally to the area in need of treatment. This may be due to, for example, local injection during surgery, local application (eg in combination with post-surgical wound dressing), injection, use of catheters, use of suppositories, or use of implants. Although it can be achieved, these means are not limited. The implant is a porous, non-porous, or gelatinous material;
For example, it includes a shearal membrane or a membrane such as a fiber. In one embodiment, administration can be by direct injection into a cancer, tumor, or neoplasm, or site of tissue (or pre-stage site) prior to neoplasia. In another embodiment, administration can be by direct injection at the site of viral infection, tissue or organ transplant, or at the site of autoimmune response (or the site of the previous stage).

In certain embodiments, it may be desirable to introduce one or more tricyclic heterocyclic compounds into the central nervous system by any suitable route, including intraventricular and intrathecal injection. Intraventricular injection can be facilitated by an intraventricular catheter coupled to a reservoir, such as, for example, an Ommaya reservoir.

Transpulmonary administration can also be utilized, for example, by use of an inhaler or nebulizer and formulation with an aerosolizing agent, or by perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the tricyclic heterocyclic compound is a conventional binder and carrier,
For example, it can be formulated as a suppository using triglyceride.

In another embodiment, the tricyclic heterocyclic compound can be delivered in vesicles, particularly in liposomes (Langer, Science 249: 1527-1533 (1990); Treat et al., "Liposomes
in the Therapy of Infectious Disease and
Cancer, edited by Lopez-Bellestein and Fidler, Lis, New York, 353-36
5 pages (1989); Lopez-Bellestein
, Supra, see pages 317-327; generally see supra publications).

In yet another embodiment, the tricyclic heterocyclic compound can be delivered in a controlled release system. In one embodiment, a pump can be used (Langer, supra;
Sefton, CRC Crit. Ref. Biomed. Eng. 14:
201 (1987); Buchwald et al.,
Surgery 88: 507 (1980); Saudek et al.
t al. ), N.E. Engl. J. et al. Med. 321: 574 (1989)). In another embodiment, a polymeric material can be used ("Medii").
cal Applications of Controlled Release ",
Edited by Langer and Wise, CRC Pres. (1974), Boca Raton, Florida, USA; “Controlled
Drug Bioavailability, Drug Product Design
n and Performance ", Smolen and Ball (B
all), New York, Wiley (1984); Ranger and Peppas, J. Am. Macromol. Sci. Re
v. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228: 190 (19).
85); During et al., Ann. Neurol. 25
: 351 (1989); Howard et al., J. MoI. Ne
urosurg. 71: 105 (1989)). In yet another embodiment, a controlled release system is placed proximate to a tricyclic heterocyclic compound target (eg, the brain),
Thus, the required amount can be a fraction of the systemic dose (e.g. Goodson (
Goodson), “Medical Applications of Con”
trolled Release ", Vol. 2, pages 115-138 (1984)). Reviewer of Langer (Science 249: 1527-1)
Other controlled release systems discussed on page 533 (1990)) can also be used.

The composition of the invention comprises an effective amount of a tricyclic heterocyclic compound and a pharmaceutically acceptable carrier.
In one embodiment, the term “pharmaceutically acceptable” is approved by a federal supervisory authority or state government for use in animals, more specifically humans,
Or is listed in the United States Pharmacopeia or other generally accepted pharmacopoeia. The term “carrier” refers to a diluent, adjuvant, administered with a tricyclic heterocyclic compound,
Refers to an excipient or vehicle. Such pharmaceutical carriers can be liquids such as water and oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). The pharmaceutical carrier can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliaries, stabilizers, thickeners, lubricants, and colorants may be used. When administered to a patient, the tricyclic heterocyclic compound and the pharmaceutically acceptable carrier can be sterile. In one embodiment, water is the carrier when the tricyclic heterocyclic compound is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc,
Excipients such as sodium chloride, dry skim milk, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20 are included. The compositions of the present invention can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

The composition of the present invention is a solution, suspension, emulsion, tablet, pill, pellet, capsule,
Liquid-containing capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays,
It can take the form of a suspension, or any other form suitable for use. In one embodiment, the pharmaceutically acceptable carrier is a capsule (see, eg, US Pat. No. 5,698,155). Other examples of suitable pharmaceutical carriers are E. W. Martin (E.
W. Martin) "Remington's Pharmaceutical"
Sciences ".

The phrase “pharmaceutically acceptable salt” as used herein includes salts of acidic or basic groups that may be present in the compounds used in the compositions of the invention. However, it is not limited to these. The tricyclic heterocyclic compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. For such basic compounds, the acids that can be used to prepare pharmaceutically acceptable acid addition salts are non-toxic acid addition salts, ie, salts that contain pharmacologically acceptable anions (sulfates,
Citrate, maleate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotine Acid salt, acetate salt,
Lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisate, Fumarate, gluconate, glucaronate, saccharide, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, mesylate Salts, hydroxyethyl sulfonates, and pamonates (ie, including but not limited to 1,1′-methylene-bis- (2-hydroxy-3-naphthoic acid)). The tricyclic heterocyclic compound contained in the composition of the present invention containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. The compounds contained in the compositions of the present invention that are acidic in nature are capable of forming basic salts with various pharmaceutically or cosmetically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, in particular, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

In another embodiment, the tricyclic heterocyclic compound of the present invention is formulated as a pharmaceutical composition adapted for intravenous administration to humans according to routine procedures. Typically, tricyclic heterocyclic compounds for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary
The composition can also include a solubilizer. Compositions for intravenous administration can optionally contain a local anesthetic such as lignocaine to ease pain at the site of the injection. In general, the ingredients are combined in a sealed container (eg, an ampoule or sachet with the amount of active ingredient displayed) separately or mixed together as a unit dosage form, eg, a lyophilized powder or Supplied as a water free concentrate. Where the tricyclic heterocyclic compound is administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the tricyclic heterocyclic compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
Orally administered compositions provide one or more optional drugs, eg sweeteners such as fructose, aspartame, or saccharin; peppermint, winter green oil, or cherry to provide an easy to take preparation Perfumes such as; colorants; and preservatives. In addition, if in the form of a tablet or pill, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract and provide a sustained action over a longer period of time. A selectively permeable membrane surrounding a highly permeable driving compound is also suitable for orally administered tricyclic heterocyclic compounds. In these basic technologies, the liquid from the environment surrounding the capsule is absorbed by the driving compound, which swells and pushes the drug or drug composition out of the opening. These delivery-based technologies can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, or magnesium carboxylate. Such carriers can be pharmaceutical grade.

The amount of a tricyclic heterocyclic compound that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, but can be determined by standard clinical techniques. In addition, optionally in vitro to help identify the optimal dosage range.
A ro assay or an in vivo assay can be utilized. The exact dose utilized in the composition will also depend on the route of administration and the severity of the disease or disorder and should be determined according to the judgment of the physician and the circumstances of each patient. However, suitable effective dosage ranges for intravenous administration are generally about 0.1 to about 5 mg, preferably about 0.5 to about 3 mg of a tricyclic heterocyclic compound per kilogram of body weight. is there. In certain embodiments, i. v.
The dosage is from about 0.1 to about 0.5 mg / kg, from about 0.3 to about 0.8 mg / kg, from about 0.8 to about 1.2 mg / kg, from about 1.2 to about 2.0 mg / kg Or about 2.0 to about 3.0 mg / k
g (or equivalent dose expressed as per square meter of body surface area). As another example, using a dose of about 8 to about 500 mg without adjustment for patient weight or body surface area, i. v. It is also possible to obtain a dosage range suitable for administration. Suitable dosage ranges for intranasal administration are generally about 0.01 pg to 1 mg per kg body weight. Suppositories generally contain one or more tricyclic heterocyclic compounds of 0.5% to 10% of body weight, alone or in combination with another therapeutic agent. Oral compositions can include from about 10% to about 95% of body weight of one or more tricyclic heterocyclic compounds, alone or in combination with another therapeutic agent. In certain embodiments of the invention, suitable dosage ranges for oral administration are generally about 0.1 to about 20 mg per kg body weight, preferably about 0.5 to about 10 mg, and more preferably about An equivalent dose expressed as 1 to about 5 mg of a tricyclic heterocyclic compound, or per square meter of body surface area. In certain embodiments, the oral dose is about 1 to about 7.5 mg / kg.
About 7.5 to about 10 mg / kg, about 10 to about 12.5 mg / kg, about 12.5 to about 15 m
g / kg, or about 15 to about 20 mg / kg (or equivalent dose expressed as per square meter of body surface area). In another embodiment, a suitable dose for oral administration is from about 20 to about 2000 mg, without adjustment for patient weight or body surface area. Other effective doses can be extrapolated from dose-response curves determined from in vitro or animal model test systems. Such animal models and systems are well known in the art.

The present invention also provides a pharmaceutical pack or pharmaceutical kit comprising one or more containers containing one or more tricyclic heterocyclic compounds. Such a container is optionally a government-designated form of precaution that oversees the manufacture, use or sale of a pharmaceutical or biological product, which is manufactured, used or administered for human administration. There may be a note reflecting that the sale is authorized. In certain embodiments, for example when administered for the treatment or prevention of cancer, the kit of the invention is used for the treatment of cancer or neoplastic disease administered in combination with a tricyclic heterocyclic compound. One or more useful chemotherapeutic agents may also be included.

The tricyclic heterocyclic compounds of the present invention are preferably assayed in vitro and then in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
For example, in vitro assays can be used to determine whether administration of a particular tricyclic heterocyclic compound or combination of tricyclic heterocyclic compounds is preferred.

In one embodiment, a patient tissue sample is cultured and expanded and contacted with a tricyclic heterocyclic compound, or otherwise administered with a tricyclic heterocyclic compound, and the tricyclic to the tissue sample is The effect of the sex heterocycle is observed and compared with the tissue that is not in contact. In other embodiments, a cell culture model is used, in which the cultured cells are contacted with a tricyclic heterocyclic compound, or otherwise administered with a tricyclic heterocyclic compound, to the tissue sample. The effect of the tricyclic heterocyclic compound is observed and compared with cells that have not been contacted. In general, lower levels of proliferation or survival of contacted cells compared to uncontacted cells indicate that the tricyclic heterocyclic compound is effective for treating a patient. For such tricyclic heterocyclic compounds, animal model systems can also be used to demonstrate efficacy and safety.

Other methods are known to those skilled in the art and are within the scope of the present invention.
5.6 Inhibition of Cancer and Neoplastic Disease The tricyclic heterocyclic compounds of the present invention are known in the art or can be used in vitro and in vitro using various assays described herein. In vivo, it can be demonstrated to inhibit tumor cell growth, cell transformation, and tumor formation. Such assays may use cancer cell line cells or cells from patients. Many assays well known in the art can be used to assess such survival and / or proliferation. For example, cell proliferation is determined by directly counting cells by measuring ( ³ H) -thymidine incorporation, or by proto-oncogenes (eg, fos, myc) or cell cycle markers (Rb, cdc2, cyclin A , D1, D2, D3, E, etc.) can be assayed by detecting changes in transcription, translation, or activity of known genes. Such protein and mRNA levels and activities can be determined by any method known in the art. For example, the protein may be a commercially available antibody (eg, many cell cycle marker antibodies are Santa Cruz Incorporated (Santa C).
ruz Inc. Can be quantified by known immunodiagnostic methods such as Western blotting or immunoprecipitation. mRNA can be quantified by methods well known and routine in the art, such as Northern analysis, RNase protection, reverse transcription polymerase chain reaction, and the like. Cell viability can be assessed by using trypan blue staining or other cell death markers or cell survival markers known in the art. Differentiation can be assessed visually based on morphological changes and the like.

The present invention provides an analysis of cell cycle and cell proliferation by various techniques known in the art. Such techniques include, but are not limited to:
As one example, bromodeoxyuridine (BRDU) uptake can be used as an assay to identify proliferating cells. This BRDU assay identifies a cell population during DNA synthesis by incorporation of BRDU into newly synthesized DNA. The newly synthesized DNA can then be detected using an anti-BRDU antibody (Hoshino et al., 1986, Int. J. Canc.
er 38, 369; Campana et al., 1988, J. Am. Immunol. Meth. 107, 79).

Cell proliferation can also be tested using ( ³ H) -thymidine incorporation (eg, Chen, J., 1996, Oncogene 13: 1395).
˜403 pages; John, J., 1995, J. Am. Biol.
Chem. 270: pages 18367-73). This assay is based on S phase D
Allows quantitative characterization of NA synthesis. In this assay, cells that synthesize DNA incorporate ( ³ H) -thymidine into newly synthesized DNA. Uptake can then be measured by techniques that are standard in the art, for example by counting radioisotopes in a scintillation counter (eg, a Beckman LS 3800 liquid scintillation counter).

Detection of proliferating cell nuclear antigen (PCNA) can also be used to measure cell proliferation. PC
NA is a 36 kilodalton protein whose expression is elevated in proliferating cells, particularly in the early G1 and S phases of the cell cycle, thus serving as a marker for proliferating cells. obtain. Positive cells are identified by immunostaining with anti-PCNA antibody (Li et al., 1996, Curr. Biol. 6).
189-199; Vasilev et al., 1995.
Year, J.M. Cell Sci. 108: 1205-15).

Cell proliferation can also be measured by counting a sample of the cell population over time (eg, counting cells daily). Cell counts are performed using a hemacytometer and a light microscope (e.g.,
HyLite ™ hemocytometer, Hausser Sciific
entific)). To obtain a growth curve for the cell population of interest, the cell number can be plotted against time. In certain embodiments, cells counted by this method are first trypan blue dye (Sigma).
a)), but as a result, living cells exclude this dye and are counted as live members of the same population.

The DNA content and / or mitotic index of a cell can be measured based on, for example, the DNA ploidy value of the cell. For example, cells in the G1 phase of the cell cycle are generally DNA
The ploidy value is 2N. Cells that have replicated DNA but have not undergone mitosis (
For example, cells in S phase) have a ploidy value higher than 2N and up to 4N DNA content. Ploidy values and cell cycle kinetics can be further measured using the propidium iodide assay (see, eg, Turner, T. et al.
), 1998, Prostate 34: 175-81). As another example, DNA ploidy can be determined by quantifying DNA foilgen staining (which binds to DNA in a stoichiometric manner) with a computerized microdensitometry staining system ( For example, Bacchus, S, 198
9 years, Am. J. et al. Pathol. 135: 783-92). In another embodiment, DNA content can be analyzed by the preparation of chromosomal spreads (Zabalou, S., 1994, Heritas. 120: 127-40; Pardue, 1994). Meth. Cell Biol.44.
: 333-351).

Cell cycle proteins (eg, CycA, CycB, CycE, CycD, cdc2,
Expression of Cdk4 / 6, Rb, p21, p27, etc.) provides critical information related to the growth status of a single cell or cell population. For example, identification in the anti-proliferative signaling pathway can be shown by induction of p21 ^cip1 . An increase in the level of p21 expression in the cells delays the cell cycle from entering G1 (Harper et al.).
1993, Cell 75: 805-816; Li et al.
1996, Curr. Biol. 6: 189-199 pages). Induction of p21 can be identified by immunostaining using specific anti-p21 antibodies that are commercially available (eg, from Santa Cruz). Similarly, cell cycle proteins can be tested by Western blot analysis using commercially available antibodies. In another embodiment, the cell population is synchronized prior to detection of cell cycle proteins. Cell cycle proteins can also be detected by FACS (fluorescence activated cell sorter) analysis using antibodies against the protein of interest.

Detecting changes in cell cycle length or cell cycle speed can also be used to measure inhibition of cell proliferation by the tricyclic heterocyclic compounds of the present invention. In one embodiment, the length of the cell cycle is measured by the doubling time of the cell population (eg, using cells that have been contacted or not contacted with one or more tricyclic heterocyclic compounds). . In another embodiment, FACS analysis is used to analyze the phase of cell cycle progression, or G1, S,
And G2 / M fractions are purified (eg, Delia, D. et al.
al. ), 1997, Oncogene 14: 2137-47).
.

The expiration of the cell cycle checkpoint and / or the induction of the cell cycle checkpoint can be tested by the methods described herein or by any method known in the art. Without limitation, a cell cycle checkpoint is a mechanism that ensures that certain cellular events occur in a certain order. Checkpoint genes are defined by mutations that cause later events to occur when early events have not been previously completed (Weinert, T. and Hartwell, Hart)
well, L.W. ), 1993, Genetics, 134: 63-80 pages). Induction or inhibition of the cell cycle checkpoint gene can be assayed, for example, by Western blot analysis or immunostaining. Expiration of a cell cycle checkpoint further means that the cell progresses past the checkpoint without specific events occurring in advance (for example, genomic DNA does not fully replicate and progresses to mitosis) ) Can be further evaluated.

In addition to the effects of expression of certain cell cycle proteins, the activity and post-translational modifications of proteins involved in the cell cycle may play an essential role in cell regulation and growth states.
The present invention provides assays for detecting post-translational modifications (eg, phosphorylation) by any method known in the art. For example, antibodies that detect phosphorylated tyrosine residues are commercially available and can be used in Western blot analysis to detect proteins with such modifications. In another example, modifications such as myristylation can be detected by thin layer chromatography or reverse phase HPLC (eg, Glover, C., 1988, Biochem. J. 250: 485). Page 91; Page, L., 1988, Biochem J .; 250
: 485-91).

The activity of signaling and cell cycle proteins and / or protein complexes is:
Often mediated by kinase activity. The present invention provides for the analysis of kinase activity by assays such as the histone H1 assay (eg, Delia, Dee et al.
D. et al. ), 1997, Oncogene 14: 2137-47).

It can be demonstrated using methods well known in the art that the tricyclic heterocyclic compounds of the present invention alter cell proliferation of cultured cells in vitro. Specific examples of cell culture models include, but are not limited to: Lung cancer includes primary cells of rat lung tumors (Swaford et al., 1997, Mol. Cell. B).
iol. 17: 1366-1374) and large cell undifferentiated cancer cell lines (Mabry et al., 1991, Cancer Cells, 3: 53-
58); colorectal cell lines (Park and Gazder (
Gazdar), 1996, J. Am. Cell Biochem. Addendum 24: 131-14
Page 1); multiple breast cancer cell lines (Hambly et al.
. ), 1997, Breast Cancer Res. Treat. 43: 247 ~
258; Gierthy et al., 1997, Chemo.
sphere 34: 1495-1505; Prasad and Church, 1997, Biochem. Biophys. Res. Com
mun. 232: 14-19); several well-characterized cell models for prostate cancer (Webber et al., 1996, Prost
ate, Part 1, 29: 386-394; Part 2, 30: 58-64
Page; and Part 3, 30: 136-142; Boulicus (Boulik)
as), 1997, Anticancer Res. 17: pp. 1471-1505); for genitourinary cancers, a continuous passage cell line of human bladder cancer (Riveiro et al.
et al. ), 1997, Int. J. et al. Radiat. Biol. 72: 11-2
Page 0); organ cultures of transitional cell carcinoma (Booth et al., 19
1997, Lab Invest. 76: 843-857) and the rat development model (Vet et al., 1997, Biochim. Biophy.
Acta 1360: 39-44); and leukemia and lymphoma established cell lines (Drexler, 1994, Leuk. Res. 18: 919.
-927 pages, Toyama, 1997, Int. J. et al. Hemato
l. 65: 309-317).

The tricyclic heterocyclic compounds of the present invention can also be demonstrated to inhibit cell transformation (or progression to a malignant phenotype) in vitro. In this embodiment,
Contacting a cell having a phenotype of the transformed cell with one or more tricyclic heterocyclic compounds;
Test for changes in characteristics associated with the transformed phenotype (a series of in vitro characteristics associated with in vivo tumorigenicity). The changes include, for example, colonization in soft agar, rounded cell morphology, loose adhesion to the substrate, loss of contact inhibition, loss of anchorage dependence, proteases such as plasminogen activator Release, increased sugar transport, decreased serum requirement, or expression of fetal antigens (such as Luria et al.
al. ), 1978, General Virology, 3rd edition, John Wiley & Sons, New York, USA, 4
36-446), but is not limited thereto.

In one embodiment, the tricyclic heterocyclic compound is cytotoxic.
In another embodiment, the tricyclic heterocyclic compound exhibits a higher level of cytotoxicity in cancer cells than in non-cancer cells.

Loss of invasiveness or decreased adhesion can also be used to demonstrate the anticancer effects of tricyclic heterocyclic compounds. For example, an important feature of metastatic cancer formation is the ability of precancerous or cancerous cells to leave the primary site and establish new growing colonies at the second site. The ability of cells to invade surrounding sites reflects the potential for a cancerous condition. Invasion loss can be measured by various techniques known in the art, for example, induction of cell-cell adhesion mediated by E-cadherin. Such E-cadherin-mediated adhesion can lead to phenotypic reversal and loss of invasiveness (Hosick et al. (
Hordijk et al. ), 1997, Science 278: 1464-6.
6 pages).

Invasive loss can be further tested by inhibition of cell migration. A variety of 2D and 3D cell matrices are commercially available (Calbiochem-Novabiochem Corp., San Diego, Calif., USA).
Alternatively, cell migration into the matrix can be tested by microscopy, time-lapse photography or videography, or any method in the art that allows measurement of cell migration. In related embodiments, loss of invasiveness is tested by response to hepatocyte growth factor (HGF). HGF-induced cell distribution is determined by Madin-Derby.
-Darby) correlates with the invasiveness of cells such as canine kidney (MDCK) cells. This assay identifies a cell population that has lost the cell's dispersive activity in response to HGF (Hordijk et al., 1997, Science 278: 14).
64-page 66).

As another example, the loss of invasiveness can be determined using a chemotaxis chamber (Neuroprobe / Precision B, Neuroprobe / Precision Biochemicals, Inc.
iochemicals inc. ) Measured by cell migration through [Vancouver, British Columbia, Canada].
In such an assay, the chemoattractant is incubated on one side of the chamber (eg, in the lower chamber) and the cells are placed on a filter separating the opposite side (eg, the upper chamber). In order for cells to pass from the upper chamber to the lower chamber, the cells must actively move through small holes in the filter. Checkerboard analysis of the number of migrated cells can then be correlated with invasiveness (eg, Onishi, T. 1993, Biochem. Biophys. R).
es. Commun. 193: 518-25).

The tricyclic heterocyclic compounds of the present invention can also be demonstrated to inhibit tumor formation in vivo. A vast number of animal models of hyperproliferative disorders (including tumorigenesis and metastatic spread) are known in the art (Isselba et al.
cher et al. ) "Harrison's Principals of I"
“National Medicine, 13th Edition”, McGraw-Hill, New York, USA, page 1814, chapter 317 “Principals
of Neoplasia ", Table 317-1, and Lovejoy et al. (Lovejoy)
et al. ), 1997; Pathol. 181: See pages 130-135). Specific examples include: For lung cancer, tumor nodule transplantation into rats (Wang et al., 1997, Ann. Thorac. Surg.
64: 216-219) or establishment of lung cancer metastasis in NK cell-depleted SCID mice (Yono and Sone, 1997, Cancer and chemotherapy, 2
4: 489-494). For colon cancer, colon cancer transplantation of human colon cancer cells into nude mice (Gutman and Fiddler, 19
1995, World J. Org. Surg. 19: 226-234), a cottontail tamarin model of human ulcerative colitis (Warren, 1996, Alignment.
Pharmacol. Ther. 10 Addendum 12: 45-47) and a mouse model with a mutation in the tumor suppressor of adenomatous polyposis (Polakis)
1997, Biochim. Biophys. Acta 1332: F127-F1
47). For breast cancer, a breast cancer transgenic model (Dancoat (D
anchor and Muller, 1996, Cancer Trea
t. Res. 83: 71-88; Amundaditir et al.
et al. ), 1996, Breast Cancer Res. Treat. 3
9: 119-135) and chemical induction of tumors in rats (Russ
o) and Russo, 1996, Breast Cancer Res.
Treat. 39: 7-20 pages). For prostate cancer, chemically derived rodent and transgenic rodent models, and human xenograft models (Royai, 1996, Semin. Oncol. 23: 35-40)
. For genitourinary cancer, rat and mouse-induced bladder neoplasia (Oy
asu), 1995, Food Chem. Toxicol 33: 747-755) and human transitional cell carcinoma xenografts in nude mice (Jarr et al. (Jarr et al.
ett et al. ), 1995, J. Am. Endourol. 9: 1-7 pages). As for hematopoietic cancer, allogeneic bone marrow transplanted in animals (Appelbaum (
Appelbaum), 1997, Leukemia 11 (Appendix 4): S15-S1.
Page 7). Furthermore, there are reports on general animal models that can be applied to many types of cancer, such as p53-deficient mouse models (Donehower, 1
996, Semin. Cancer Biol. 7: 269-278), Min
Mouse (Shoemaker et al., 1997, Bio
chem. Biophys. Acta, 1332: F25-F48), and immune responses against tumors in rats (Frey, 1997, Methods,
12: 173-188 pages), but is not limited to these.

For example, a tricyclic heterocyclic compound is administered to a test animal, preferably a test animal that is predisposed to develop certain types of tumors, followed by administration of the tricyclic heterocyclic compound. Can be examined for a decrease in the incidence of tumor formation compared to non-control. As another example, a tricyclic heterocyclic compound may be added to a tumor-bearing test animal (eg, an animal whose tumor is induced by the introduction of malignant cells, neoplastic cells, or transformed cells, or by administration of a carcinogen). Followed by the tumor of the test animal can be examined for tumor regression compared to a control not receiving the tricyclic heterocyclic compound.

5.7 Treatment or prevention of cancer or neoplastic disease further comprising the step of administering chemotherapy or radiation therapy, including any disease or disorder characterized by neoplasm, tumor, metastasis, or uncontrolled cell growth ( A cancer or neoplastic disease, which is not limited to these, can be treated or prevented by administration of an effective amount of a tricyclic heterocyclic compound.

In certain embodiments, the methods of the invention for treating or preventing cancer or neoplastic disease include methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosourea, cisplatin , Carboplatin, mitomycin, decarbazine, procarbazine, etoposide,
Anticancer chemotherapeutic agents such as (but not limited to) camptothecin, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, pricamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, and docetaxel The method further includes the step of administering. In another embodiment, the anticancer agent is one or more of those presented below in Table 1.

In other embodiments, the method for treating or preventing cancer or neoplastic disease further comprises administering radiation therapy and / or administering one or more chemotherapeutic agents,
In one embodiment, the cancer has not been found to be resistant. The tricyclic heterocyclic compounds can be administered to patients who are also undergoing surgery as a treatment for cancer.

In another specific embodiment, the present invention provides a method for treating or preventing cancer that has been shown to be resistant to treatment with chemotherapy and / or radiation therapy.

In certain embodiments, an effective amount of a tricyclic heterocyclic compound is administered concurrently with chemotherapy or radiation therapy. In another specific embodiment, the chemotherapy or radiation therapy is at least one prior to or after administration of the tricyclic heterocyclic compound, eg, after or prior to administration of the tricyclic heterocyclic compound. It is given at the time of 5 hours, 12 hours, 1 day or 1 week.

If the tricyclic heterocyclic compound is administered before chemotherapy or radiation therapy, the chemotherapy or radiation therapy is administered while the tricyclic heterocyclic compound is exerting its therapeutic or prophylactic effect. Is done. If chemotherapy or radiation therapy is given before the tricyclic heterocyclic compound is administered, the tricyclic heterocyclic compound is administered while chemotherapy or radiation therapy is exerting its therapeutic effect. The

A chemotherapeutic agent can be administered in a series of treatments, and any one or combination of the chemotherapeutic agents listed above can be administered. For radiation therapy, any radiation therapy protocol can be used depending on the type of cancer to be treated. For example (but not as a limitation), x-ray irradiation can be given; in particular high energy megavolts (irradiation higher than 1 MeV energy) can be used for deep tumors. Also, electron beam and normal voltage x-ray irradiation can be used for skin cancer. Radioisotopes that emit gamma radiation (radioactive isotopes of radium, cobalt, and other elements) can also be used to irradiate tissue.

Furthermore, the present invention may be used when chemotherapy or radiation therapy has been found to be too toxic for the patient being treated or may be too toxic (eg, producing unacceptable or intolerable side effects). As an alternative to the chemotherapy or radiation therapy,
Methods of treating cancer or neoplastic diseases using tricyclic heterocyclic compounds are provided. Patients treated with the compositions of the present invention may optionally be treated with other cancer treatments (eg, surgery, radiation therapy, or chemotherapy), but any treatment is acceptable or tolerable. It depends on whether it is known.

5.8 Treatable or Preventable Cancer and Neoplastic Diseases Cancer or neoplastic diseases and related disorders that can be treated or prevented by administration of tricyclic heterocyclic compounds are listed in Table 2. Including but not limited to (for a review of such disorders, see Fishman et al.
), 1985, "Medicine second edition", J. Bee. Lippincott (J
. B. Lippincott Co. ) [Philadelphia
) Location].

In certain embodiments, the cancer, malignancy or proliferative change (eg, dysplasia and dysplasia), or hyperproliferative disorder is ovarian, breast, colon, lung, skin, pancreas, prostate, bladder Or treated or prevented in the uterus. In other specific embodiments,
Sarcoma, melanoma, or leukemia is treated or prevented.

In another embodiment, the tricyclic heterocyclic compound is a prostate cancer (more preferably hormone insensitive), neuroblastoma, lymphoma (preferably follicular or diffuse large cell type B).
Cell), breast cancer (preferably estrogen receptor positive), colorectal cancer, endometrial cancer, ovarian cancer, lymphoma (preferably non-Hodgkin), lung cancer (preferably small cell cancer)
Or for the treatment or prevention of testicular cancer (preferably germ cells).

In another embodiment, the tricyclic heterocyclic compound is a prostate (more preferably hormone insensitive), neuroblastoma, lymphoma (preferably follicular or diffuse large B cell), breast (preferably Cells derived from cancer or neoplasm such as colorectal, endometrium, ovary, lymphoma (preferably non-Hodgkin), lung (preferably small cells), or testis (preferably germ cells) Used to inhibit the growth of

In certain embodiments of the invention, the tricyclic heterocyclic compound is used to inhibit the growth of cells derived from the cancer or neoplasm described in Table 2 or herein.
5.10 Demonstration of Inhibition of Viruses and Viral Infections Tricyclic heterocyclic compounds of the present invention are known in the art or can be generated in vitro or using various assays described herein. It can be demonstrated in vivo to inhibit the replication or infectivity of viruses or cells infected with viruses. In certain embodiments, such assays use cells of a cell line or cells from a patient. In certain embodiments, the cells may be infected with the virus prior to or during the assay. The cell may be contacted with a virus. In certain other embodiments, the assay can utilize a cell-free virus culture.

In one embodiment, the tricyclic heterocyclic compound is a viral reaction in vitro (
For example, a cultured cell showing an indicator of inclusion body formation) is contacted with a tricyclic heterocyclic compound, and the level of the indicator in the cell contacted with the tricyclic heterocyclic compound is not so contacted By comparing with the level of the indicator in the medium, it is demonstrated to have the activity of treating or preventing viral diseases. Here, a lower level in the contacted cell indicates that the tricyclic heterocyclic compound has activity to treat and prevent viral diseases. Cell models that can be used for such assays include, but are not limited to: T lymphocyte viral infection model (Selin et al.)
1996, J. Am. Exp. Med. 183: 2489-2499). Hepatitis B infection model of dedifferentiated liver cancer cells (Raney et al., 1997
Year, J.M. Virol. 71: 1058-1071). Viral infection model of cultured salivary gland epithelial cells (Clark et al., 1994, Autoi
mmunity 18: 7-14 pages). Synchronous HIV- of CD4 ⁺ lymphoid cell line
1 infection model (Wainberg et al., 1997, Vi
rology 233: pages 364-373). Respiratory epithelial cell viral infection model (
Stark et al., 1996, Human Gene The.
r. 7: 1669-1681); and NIH-3T3 cell amphotropic (
(Broad host) retroviral infection model (Morgan et al., 1
995, J. Am. Virol. 69: 6994-7000 pages).

In another embodiment, the tricyclic heterocyclic compound is a test animal with signs of viral infection (eg, characteristic respiratory signs in an animal model), or does not show a viral response but subsequently induces a viral response Having activity to treat or prevent viral diseases by administering tricyclic heterocyclic compounds to test animals loaded with drugs and measuring changes in viral response after administration of tricyclic heterocyclic compounds Is demonstrable. At this time,
Reduction of viral response or prevention of viral response indicates that the tricyclic heterocyclic compound has activity to treat or prevent viral diseases. Animal models that can be used for such assays include, but are not limited to: Guinea pig model for respiratory viral infections (Kudlacz and Knippenberg, 1995, Inflamm. Res. 44: 105-1
10 pages). Mouse model for influenza virus infection (Dobb et al.
s et al. ), 1996, J. Am. Immunol. 157: 1870-1877 pages). Lamb model for respiratory syncytial virus infection (Masot et al.
al. ), 1996, Zentralbl. Veterinarmed. 43:23
3 to 243 pages). A mouse model for neurotropic virus infection (Bern et al.
a et al. ), 1996, Virology 223: 331-343)
. A hamster model for measles infection (Fukuda et al., 19
94, Acta Otalyngol. Addendum 514: 111-
116 pages). Mouse model for encephalomyocarditis infection (Hirasawa et al.
et al. ), 1997; Virol. 71: 4024-4031). And mouse models for cytomegalovirus infection (Orange and Byron, 1996, J. Immunol. 156: 1138-114
2 pages). In certain embodiments of the invention, two or more tricyclic heterocyclic compounds are administered to the test animal, virus, or virus-infected cell.

5.11 Viruses and viral infections Viruses and viral infections that can be treated or prevented by administering a tricyclic heterocyclic compound include, but are not limited to, those listed in Table 3. For example, DNA viruses such as hepatitis B virus and hepatitis C virus; parvoviruses such as adeno-associated virus and cytomegalovirus;
For example, papillomavirus, polyomavirus, and SV40; adenovirus;
Herpes viruses such as type I herpes simplex virus (HSV-I), type II herpes simplex virus (HSV-II), and Epstein-Barr virus; pox viruses such as small pox and vaccinia viruses; and RNA viruses For example, type I human immunodeficiency virus (HIV-I), type II human immunodeficiency virus (
HIV-II), type I human T cell leukemia virus (HTLV-I), type II human T cell leukemia virus (HTLV-II), influenza virus, measles virus, rabies virus, Sendai virus, picornavirus, eg, polio Virus, coxsackie virus, rhinovirus, reovirus, togavirus, eg rubella virus (rubella)
And Semliki Forest virus, arbovirus, and hepatitis A virus.

In one embodiment of the invention, the tricyclic heterocyclic compound is used to treat or prevent viral infections associated with the viruses listed in Table 3. In another embodiment, tricyclic heterocyclic compounds are used to inhibit the replication or infectivity of the viruses listed in Table 3. In yet another embodiment, the tricyclic heterocyclic compound is used to inhibit the growth of cells infected with the viruses listed in Table 3.

5.12 Prodrugs The present invention also includes the following prodrugs of the tricyclic heterocyclic compounds of the present invention.

In certain embodiments, the present invention provides a method for treating cancer in a patient comprising administering to the patient an effective amount of compound 66 or compound 67. In certain embodiments, the present invention provides a method for treating a viral infection in a patient comprising administering to the patient an effective amount of compound 66 or compound 67. Illustrative methods for synthesizing compound 66 or compound 67 are described in Example 4, respectively.

The present invention also provides prodrugs of the tricyclic heterocyclic compounds of the present invention. Prodrugs can yield tricyclic heterocycles of the invention that are active under biological conditions (in vitro or in vivo) by hydrolysis, oxidation, or other reactions,
Derivatives of tricyclic heterocyclic compounds are included. Examples of prodrugs include in vivo hydrolysable moieties, such as in vivo hydrolysable amides, in vivo hydrolysable esters, in vivo hydrolysable carbamates, in vivo hydrolysables. Examples include, but are not limited to, carbonates and derivatives and metabolites of the compounds of the invention including phosphate analogs that are hydrolysable in vivo. In certain embodiments, the prodrug of a tricyclic heterocyclic compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. This carboxylic acid ester is simply formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs are generally known in a well-known manner, eg, “Burg
er's Medicinal Chemistry and Drug Discov
ery, 6th edition "(Donald J. Abraham
Ed., 2001, Wiley) and "Design and Appl.
ication of Prodrugs "(H. Bundga
ard), 1985, Harwood Academic Publishers (Harwood)
Academic Publishers Gmfh)). The in vivo hydrolyzable moiety of the tricyclic heterocyclic compound does not interfere with the biological activity of the compound (1) but is beneficial to the compound in vivo, such as uptake, duration of action, or It is possible to confer an onset of action; or (2) convert to a biologically inactive but biologically active compound in vivo. Examples of esters that can be hydrolyzed in vivo include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters, and choline esters. Examples of amides that can be hydrolyzed in vivo include lower alkyl amides, α
-Including but not limited to amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of carbamates that can be hydrolyzed in vivo include, but are not limited to, lower alkyl amines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

  6). Example

  Compound 1 hydrochloride was prepared as shown in Scheme 2a below.

[Preparation of 5-bromo-3-methoxypyrrole-2-carboxaldehyde B]
Phosphoryl bromide (220 mol%, 5.58 g) in dry dichloromethane (20 mL)
) Was added dropwise over 2 minutes with DMF (220 mol%, 1.4 mL).
The resulting reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to a Vilsmeier (Vi
lsmeyer) complex was obtained as a white solid. After drying for 1 hour in vacuo, the white solid was suspended in dry dichloromethane (20 mL) and cooled to 0 ° C. Dichloromethane (1
4-methoxy-3-pyrrolin-2-one (A) (1 g, 8.84 mmol) in 0 mL)
Of the reaction mixture was added dropwise and the resulting reaction mixture was stirred at 0 ° C. for 30 minutes, then at room temperature for 2 minutes.
Stir for 0 hour. The mixture was poured onto ice (75 mL) and NaOH 4N aqueous solution (50 mL).
), Diluted with EtOAc (100 mL) and stirred for 15 min. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (3 × 20
0 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude residue. The crude residue was 0-20% using silica gel flash column chromatography.
Purification as a gradient elution of EtOAC / hexanes afforded compound B as a white solid. NMR
¹ H (300 MHz, CDCl ₃ ): δ (ppm) 3.95 (s, 3H); 5.90 (
s, 1H); 9.30 (s, 1H), 9.92 to 10.34 (bs, 1H). m / z: 2
05.1 [M + 1].

[Preparation of 5-indolyl-3-methoxypyrrole-2-carboxaldehyde C]
Compound B (120 mg, 0.60 mmol), N-Boc-indoleboronic acid (15
0 mol%, 230 mg), barium hydroxide hexahydrate (150 mol%, 278 mg) and dichloro (diphenylphosphinoferrocene) palladium (II) (10 mol%, 48 m
To the mixture of g) was added a degassed 4: 1 DMF / water mixture (15 mL, 0.04 M). The mixture was stirred at 80 ° C. for 3 hours and then diluted with EtOAc (20 mL) and water. The resulting solution was filtered through a pad of Celite® and the layers were separated. The organic layer was washed with brine (3 × 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a crude residue. The crude residue was purified using silica gel flash column chromatography as a gradient elution of 0-75% EtOAC / hexanes to give compound C as a green solid. ¹ H NMR (300 MHz, CD ₃ OD): δ (ppm)
3.95 (s, 3H); 6.40 (s, 1H); 6.95 (s, 1H); 7.00 (t,
1H); 7.15 (t, 1H); 7.35 (d, 1H); 7.54 (d, 1H); 9.3
3 (s, 1H). m / z: 241.17 [M + 1].

[Preparation of Compound 1 Hydrochloride]
Compound C (2 mg, 8 μmol) and 2,4-dimethylpyrrole (100 mol%, 0
. A drop of saturated methanolic HCl was added to a solution of 8 mg) in methanol (0.4 mL). The resulting dark red solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting residue was dried in vacuo to give compound 1 hydrochloride. NMR ¹ H (300 MHz, CDC
l ₃ ): δ (ppm) 2.33 (s, 3H); 2.63 (s, 3H); 4.04 (s, 3
H); 6.10 (s, 1H); 6.30 (s, 1H); 7.07 to 7.16 (m, 3H)
7.30 (t, 1H); 7.60 (d, 2H); 12.22-12.38 (bs, 1H);
); 12.90-13.10 (bs, 1H). m / z: 319.17 [M + 1].

[Preparation of Compound 1 Tartrate]
About 1 gram of Compound 1 hydrochloride was dissolved in 100 mL of ethyl acetate and washed with 5% NaOH solution (2 × 20 mL) (until the aqueous layer was pH 9-10). The resulting organic layer was then separated, dried and evaporated to dryness to give compound 1 (free base).

About 5 grams of Compound 1 was transferred to a lyophilization flask and 100 ml of acetonitrile was added. The resulting orange suspension was stirred for 1 minute. Then 50 ml distilled water and 2.36 g L-tartaric acid were added. The resulting red-purple mixture was stirred for 5 minutes. An additional 50 ml of distilled water was added and the thick brown suspension was stirred for 5 minutes. The lyophilization flask containing the suspension was immediately cooled to −53 ° C. to −78 ° C. to freeze the suspension. The flask was then placed in a lyophilizer and evacuated. The flask was maintained at a pressure of less than 50 m Torr (0.07 mbar) until the material was dried to give Compound 1 tartrate as a red-brown amorphous powder.

  Compound 1 hydrochloride was also prepared as shown in Scheme 2b below.

[Synthesis of 5-bromo-3-methoxypyromethene (B ′)]
To a mixture of diethylformamide (3 eq, 5.8 mL) and chloroform (5 mL) at 0 ° C. was added dropwise a solution of phosphorus oxybromide (2.5 eq, 12.6 g) in chloroform (15 mL). It was. The resulting suspension was stirred at 0 ° C. for 30 minutes and the solvent was removed by centrifugal evaporation to give the Vilsmeier complex as a white solid. After drying in vacuo for 20 minutes, the solid was treated with chloroform (10 mL) and cooled to 0 ° C. 4-Methoxy-3-pyrrolin-2-one (A, 2 g) in chloroform (20 mL)
17.7 mmol) was added dropwise and the mixture was allowed to warm to room temperature and then heated at 60 ° C. for 5 h. The mixture was poured into ice (75 mL) and the pH of the aqueous solution was adjusted to pH 7-8 with NaOH (2N). EtOAc (40 mL) was added to the resulting precipitate and the mixture was filtered through Celite® to remove a black solid containing the phosphate salt.

The two layers were separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with brine (3 × 200 mL), dried over Na ₂ SO ₄ , filtered, and the solvent was removed by centrifugal evaporation to give the crude enamine intermediate B ′.

The residue was padded with silica gel (50 mL) eluting with 10% EtOAC / hexane.
To obtain enamine as an oil. Enamine becomes a beige solid when dried in vacuum.

Yield: 3.20 g, 70%.
M / Z: 260.1 [M + 1]
RMN ¹ H (300 MHz, CDCl ₃ ): δ (ppm) 1.24 to 1.37 (m,
6H); 3.31-3.46 (q, 2H); 3.76 (s, 3H), 4.03-4.18
(Q, 2H); 5.58 (s, 3H); 6.98 (s, 3H).

[Synthesis of 5-indolyl-3-methoxypyrrole-2-carboxaldehyde (C)]
To a degassed solution of toluene (1.5 mL) was added Pd (OAc) ₂ (0.1 equivalent, 86 mg) and PPh ₃ (0.45 equivalent, 456 mg). The mixture immediately became light yellow and was stirred at 70 ° C. for 20 minutes under N ₂ .

5-Bromo-3-methoxypyromethene (B ′, 10% water / dioxane (15 mL))
1.17 g, 4.51 mmol) and N-Boc-indoleboronic acid (B ″, 1.1
Eq, degassed solution of 1.29 g), and purged with _{N 2.} This solution was added to Pd in toluene.
Transfer to a suspension of (PPh ₃ ) ₄ followed by the addition of Na ₂ CO ₃ (3.0 eq, 1.23 g). The mixture was stirred at 100 ° C. for 3 hours, then NaOMe (1.0 eq, 244 mg
). The mixture was stirred at 100 ° C. for 15 minutes and then further NaOMe (1
. 0 equivalent, 244 mg) and stirred at 100 ° C. for 10 minutes.

The mixture was poured into water (100 mL), the pH of the solution was lowered to pH 7 using 2N HCl, and the mixture was stirred for 10 minutes. The brown precipitate was collected by filtration through a fritted disc funnel and washed with water (2 × 50 mL). The precipitate was dissolved in acetone and the solvent was removed by centrifugal evaporation. The resulting solid was dissolved in 5 mL CHCl ₃ and Et ₂ O (1
The solution was allowed to stand for 5 minutes until a yellow solid was obtained, which was filtered through a fritted disc funnel. The yellow solid was washed with 10 mL CHCl ₃ and then 2 × 1
Washed with 0 mL Et ₂ O.

Thus, the desired 5-indolyl-3-methoxypyrrole-2-carboxaldehyde (C) is obtained as a yellow solid and used without further purification.
Yield: 807 mg, 75%.

M / Z: 241.17 [M + H ⁺ 1]
RMN ¹ H (300 MHz, CD ₃ OD): δ (ppm) 3.95 (s, 3H); 6
. 40 (s, 1H); 6.95 (s, 1H); 7.00 (t, 1H); 7.15 (t, 1
H); 7.35 (d, 1H); 7.54 (d, 1H); 9.33 (s, 1H).

[2,4-Indolyl-3-methoxypyrrole-2-carboxaldehyde (C) 2,4-
Condensation with dimethylpyrrole]
5-Indolyl-3-methoxypyrrole-2-carboxaldehyde (C, 200 mg,
To a suspension of 0.83 mmol) and 2,4-dimethylpyrrole (1.1 eq, 94 μL) in methanol (8.3 mL) was added a solution of methanolic HCl (200 μL). The solution immediately turned dark pink and was stirred at room temperature for 2 hours. The solvent was removed by centrifugal evaporation and the solid was dissolved in EtOAc (30 mL). The organic layer is washed with aqueous Na
Wash with HCO ₃ (saturated, 2 × 60 mL), brine (2 × 60 mL) and dry Na ₂ CO
Dry with ₃ , filter, and concentrate by evaporation.

The product was purified by column chromatography on silica gel with a 0-30% gradient of Et.
Purified using OAC / hexane as eluent.
Yield: 237 mg, 90%.

M / Z: 319.17 [M + 1]
RMN ¹ H (300 MHz, acetone-d ₆ ): δ (ppm) 2.13 (s, 3H)
2.21 (s, 3H); 4.00 (s, 3H); 5.81 (s, 1H); 6.44 (s);
, 1H); 6.88-7.22 (m, 5H); 8.02 (d, 1H).

[Effect of Compound 1 Tartrate on Cancer Cell Viability in Vitro]
To demonstrate the effect of Compound 1 tartrate on cancer cell viability, cellular ATP levels before and after treatment of selected cell lines with Compound 1 tartrate were measured. The selected cell lines were as follows. C33A cervical cancer cell, Mrc-5 normal lung fibroblast, PC-3
Human prostate cancer cell line, OVCAR-3 human ovarian cancer cell line, H460 non-small cell lung cancer cell line, A549 human lung cancer cell line, H1299 human non-small cell lung cancer cell, MCF-7 human breast cancer cell line, SW-480 Human adenocarcinoma cell line, B16-F1 mouse melanoma cell line (
American Type Culture Collection (American Type Culture)
e Collection) [Manassas, Virginia, USA]
HMEC normal breast epithelial cells (Clonetics [San Diego, Calif., USA], and ADR-RES human breast cancer cell line (NCI, Maryland, USA). The cell line was cultured in 96-well microtiter plates (PerkinElmer Life Sciences, Inc. (PerkinElmer Life).
e Sciences Inc) [Boston, Mass., USA] was seeded at a confluency such that cells reached confluence after 4 days of growth. One day after seeding, the cells were treated with various concentrations of Compound 1 tartrate. The stock solution of Compound 1 tartrate was dimethyl sulfoxide (Sigma-Aldric Incorporated (Sigma-Aldric).
h Inc. ) Prepared in [St. Louis, Mo., USA], diluted with the recommended media described above, and then added to the cells. The total amount of dimethyl sulfoxide on the cells was 1%. After 3 days of incubation, ATP levels in the cells were quantified using a luminescent ViaLight ™ detection system (Bio-Whittaker, Maryland, USA). Were plotted against the control cells (the value of the control cells was taken as 100).

As illustrated in the bar graph of FIG. 1, Compound 1 tartrate has a significantly greater effect on ATP levels in cancer cells than in normal cells. From measurements of ATP levels 72 hours after treatment with 0.5 μM Compound 1 tartrate, Compound 1 tartrate was compared to ATP levels in normal cell lines HMEC and MRC-5, compared to cancer cell lines H1299 and C33A. It was shown to be significantly effective in reducing ATP levels in
These results indicate that Compound 1 tartrate has selective cytotoxicity against cancer cells,
And has proven useful for treating or preventing cancer, particularly lung or cervical cancer.

To further demonstrate the efficacy of Compound 1 tartrate as an anticancer agent, the effect of various concentrations of Compound 1 tartrate on cellular ATP levels was evaluated in 10 different cancer cell lines. As shown in Table 1, Compound 1 tartrate is more effective than the normal breast epithelial cell line HMEC.
It was more potent in reducing cellular ATP in cancer cell lines. These results demonstrate that Compound 1 tartrate is a selective anticancer agent.

[Effect of Compound 1 Tartrate on Proliferation of Cervical Tumor Cells in Vivo]
In order to demonstrate the antitumor activity of Compound 1 tartrate in vivo, CB17 SCID / SCID mice injected with human cervical cancer cells C33A (Charles River (
Experiments were performed using Charles River (Massachusetts, USA). The resulting mouse is a model for humans with cervical cancer.

C33A human cervical cancer cells were treated with 10% fetal bovine inactivated serum (Bio-Whittaker (Maryland, USA)) and 1% penicillin-streptomycin-L-glutamine (Gibco). (Gibco [New York, USA]) supplemented with RPMI (Hyclone [Utah, USA]) at 37 ° C., 5% CO ₂ and passaged twice a week did. Cells were grown to <70% confluency and then harvested using trypsin (Bio-Wittaker, Maryland, USA). The cells were then centrifuged, washed twice using phosphate buffered saline solution (PBS), resuspended in PBS and 2 × cells per 100 μl.
10 was ^six and. Viability was tested by staining with trypan blue (Gibco [New York, USA]) and only flasks with cell viability greater than 95% were used for in vivo studies.

C33A cells were injected subcutaneously into the flank of female CB17 SCID / SCID mice. Each mouse was inoculated with a suspension of 2 × 10 ⁶ tumor cells per 150 μl on day 0. Three treatment groups of 10 each: (a) a negative control group, (b) a positive control group, and (c) a compound 1 tartrate treatment group.

Treatment started 14 days after C33A cell transplantation. Compound 1 tartrate once a day,
IV was administered at a dose of 4.5 mg / kg for 5 consecutive days. Compound 1 tartrate is 5% dextrose (Abbott Laboratories [Abbott Laboratories]
Quebec, Canada]) and 2% polysorbate 20 (Sigma) [
Freshly prepared daily in vehicle solution from St. Louis, Missouri, USA. The negative control group was treated with vehicle alone. The injection volume was 150 μl for both the Compound 1 tartrate treated group and the negative control group. The positive control group was cisplatin (once every 3 days, 5 times in total)
Sigma (St. Louis, MO, USA) was treated as a 4 mg / kg dose. Cisplatin is formulated in PBS on each injection day and is injected at an injection volume of 80 μl.
P was administered.

Mice were weighed and tumors measured on day 13 and every 2 days after treatment began.
Observation continued for 40 days after initial tumor transplantation. The changes in body weight and calculated tumor volume were plotted.

As shown in FIG. 2, mice treated with Compound 1 tartrate did not significantly lose weight, whereas the positive control group treated with cisplatin showed 28% weight loss on day 29. Two mice in the cisplatin group were 2.2 and 29 days and 32 days, respectively.
Died after weight loss of g and 7 g.

As shown in FIG. 3, treatment with Compound 1 tartrate at a dose of 4.5 mg / kg, once daily for 5 days resulted in a statistical decrease in tumor growth compared to mice treated with vehicle alone. Significant (
p <0.0001). On days 36 and 39, the average tumors of animals treated with 4.5 mg / kg of Compound 1 tartrate were significantly (p <0.001) smaller than animals treated with vehicle alone. The T / C values on the 36th and 39th days are
They were 14% and 22%, respectively. On average, no significant weight change was observed.

As shown in FIG. 3, Compound 1 tartrate significantly reduced human cervical cancer transplanted into SCID mice, which is an artificial model for human cervical cancer. Therefore, compound 1 tartrate inhibits the growth of cervical cancer in patients, particularly human patients,
And is useful for treating or preventing cervical cancer.

  [Synthesis of Compound 66 and Compound 67]

For Scheme 3, Intermediate H is prepared by Nicolau M. et al.
G. et al. ), J.M. Org. Chem. 1996, 61, 8636-8641.

Referring to Scheme 3, Intermediate H (1 g, 1.76 mmol) was converted to acetonitrile (1
8 mL), cooled to 0 ° C., and treated with a solution of hydrogen fluoride-pyridine (1.76 mL) for 5 minutes to remove the silyl group. This free primary alcohol was replaced by Jones
s) Reagent (6 mL, added over a period of 30 minutes) was used to oxidize to the carboxylic acid and the reaction was held at 0 ° C. with vigorous stirring for 1 hour. 2-propanol (4 mL)
Was added to quench the remaining Jones reagent and the mixture was stirred for an additional 10 minutes. A saturated aqueous solution of NH ₄ Cl (40 mL) and EtOAc (30 mL) were added and the layers were separated. The organic layer was washed with saturated aqueous NH ₄ Cl (2 × 40 mL), dried over anhydrous Na ₂ SO ₄ and filtered through a funnel with a sintered glass filter. The solvent is removed by centrifugal evaporation to give a yellow-green oil which is purified by silica gel column chromatography from 0 to 50.
Purification with a gradient of% EtOAc / hexane as eluent. Carboxylic acid I was isolated as a colorless oil.

Yield: 570 mg, 70%. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm
) 1.45 (s, 6H); 2.19 (s, 3H); 2.78 (s, 1H); 5.07-5
. 16 (m, 4H); 6.87 (m, 1H); 7.09 to 7.22 (m, 2H); 7.3
1 (s, 9H).

Carboxylic acid I (570 mg, 1.22 mmol) was dissolved in CH ₂ Cl ₂ (12 mL) and cooled to 0 ° C. This solution was added to oxalyl chloride (138 μL, 1.58 mmol),
Treated with DMF (50 μL) and stirred at room temperature for 1 hour. The solvent was removed by centrifugal evaporation and the residual acid chloride J was dried in vacuo for 2 hours to give a white solid.

A solution of compound 1 (309 mg, 0.98 mmol) in THF (5 mL) was cooled to 0 ° C. and treated with solid potassium hydride (155 mg, 2.94 mmol, 70% oil dispersion). The reaction was stirred at 0 ° C. for 30 minutes. Intermediate J was dissolved in THF (5 mL) and added dropwise to the compound 1 anion. The mixture was stirred at 0 ° C. for an additional 30 minutes and then quenched with saturated aqueous NaHCO ₃ (30 mL). EtOAc (15 mL) was added and the layers were separated. The organic layer was washed with brine (3 × 30 mL), dried over anhydrous Na ₂ SO ₄ , filtered through a sintered glass filter funnel, and the solvent was removed by centrifugal evaporation. The residue was purified by column chromatography on silica gel with a 0-20% gradient of EtO.
Purification was performed using Ac / hexane as an eluent to obtain a prodrug K of dibenzyl phosphate as an orange solid.

Yield: 320 mg, 42%. M / Z: 768.35 [M + 1]. ¹ H NMR (300
MHz, CDCl ₃ ): δ (ppm) 1.38 (s, 6H); 2.09 (s, 3H); 2
. 17 (s, 3H); 2.39 (s, 3H); 5.84 (s, 2H); 3.80 (s, 3
H); 4.87-4.99 (m, 4H); 5.84 (s, 1H); 6.01 (s, 1H)
6.46-6.56 (1, 2H); 6.79 (s, 1H); 6.83-6.94 (m,
3H); 7.05 to 7.13 (m, 2H); 7.15 to 7.23 (m, 4H); 7.27
˜7.35 (m, 5H); 7.36-7.45 (m, 2H); 9.93-10.31 (b
s, 1H).

Prodrug K of dibenzyl phosphate (130 mg, 0.17 mmol) in CH ₂ Cl ₂
(4 mL), treated with TMSBr (132 μL, 1 mmol) and stirred at reflux for 45 minutes. The solvent was removed by centrifugal evaporation and the residue was dried in vacuo overnight. The residue was dissolved in CH ₂ Cl ₂ (20 mL) and washed with brine (3 × 40 mL).
The organic layer is dried over anhydrous Na ₂ SO ₄ , filtered through a sintered glass filter funnel, and the solvent is removed by centrifugal evaporation to remove the deprotected phosphate prodrug 66 as a reddish orange solid. Got as.

Yield: 100 mg, 100%. M / Z: 588.28 [M + 1]. ¹ H NMR (30
0 MHz, DMSO-d ₆ ): δ (ppm) 1.43 (s, 6H); 1.84 (s, 3H)
2.38 (s, 3H); 2.71 (s, 3H); 3.55 to 3.71 (bs, 2H)
4.05 (s, 3H); 6.34 to 6.55 (m, 3H); 6.92 to 7.06 (m,
2H); 7.17 (s, 1H); 7.23 (s, 1H); 7.26-7.47 (m, 2H)
); 7.58-7.73 (d, 1H); 7.75-7.90 (d, 1H).

Referring to Scheme 4, 1,2-benzenedimethanol (L, 3 g, 21.7 mmol)
l) and TBDMSCl (2.94 g, 19.5 mmol) in CH ₂ Cl ₂ (28 mL)
), Cooled to 0 ° C., then treated with a solution of triethylamine (12.1 mL, 86.8 mmol) in CH ₂ Cl ₂ (11 mL). The mixture was stirred at room temperature for 1 hour and the solvent was removed by centrifugal evaporation. Dissolve the residue in EtOAC (30 mL),
Washed with brine (3 × 60 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and filtered through a funnel with a sintered glass filter. The solvent was removed by centrifugal evaporation to give silylated benzyl alcohol M as a colorless oil.

Yield: 4.5 g, 91%. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm)
0.06 (s, 6H); 0.80 (s, 9H); 2.99-3.19 (bs, 1H); 4
. 56 (s, 2H); 4.70 (s, 2H); 7.14-7.32 (m, 4H).

A solution of dibenzyl phosphate (3.76 g, 13.5 mmol) in CH ₂ Cl ₂ (10 mL) was treated with oxalyl chloride (1.17, 13.5 mmol) and DMF (0.5 mL). The mixture was stirred at room temperature for 1 hour, the solvent was removed by centrifugal evaporation, and the residue was dried in vacuo for 2 hours to give dibenzyl chlorophosphate as a yellowish solid. The residue was suspended in CH ₂ Cl ₂ (5 mL), cooled to 0 ° C., with a solution of benzylic alcohol M (1.7 g, 6.7 mmol) in CH ₂ Cl ₂ (5 mL), then DBU (2 .0
2 mL, 13.5 mmol, added dropwise). The mixture was stirred at room temperature for 1.5 hours and the solvent was removed by centrifugal evaporation. The residue was purified by column chromatography on silica gel with a gradient of 0-10% EtOAc / hexane as eluent.

Yield: 1.3 g, 40%. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm)
-0.01 (s, 6H); 0.83 (s, 9H); 4.65 (s, 2H); 4.87-4
. 96 (d, 4H); 4.96 to 5.06 (d, 2H); 7.07 to 7.41 (m, 14)
H).

Dibenzyl N phosphate (1.3 g, 2.53 mmol) was dissolved in acetonitrile (25 mL), cooled to 0 ° C. and treated with a solution of hydrogen fluoride-pyridine (2.5 mL) for 5 minutes to remove the silyl group. Removed. This free primary alcohol was added to the Jones reagent (5 mL, 30
Was added to the carboxylic acid, and the reaction was held at 0 ° C. with vigorous stirring for 1 hour. 2-Propanol (6 mL) was added to quench the remaining Jones reagent and the mixture was stirred for an additional 10 minutes. A saturated aqueous solution of NH ₄ Cl (40 m
L) and EtOAc (30 mL) were added and the layers were separated. The organic layer was washed with saturated aqueous NH ₄ Cl (2 × 40 mL), dried over anhydrous Na ₂ SO ₄ and filtered through a funnel with a sintered glass filter. The solvent was removed by centrifugal evaporation to give a yellow oil that was used in the next step without any purification.

Yield: 1.0 g, 98%. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm)
5.04-5.17 (d, 4H); 5.56-5.5.67 (d, 2H); 7.27-7
. 41 (m, 11H); 7.48-7.58 (m, 2H); 7.80-8.12 (m, 1
H).

Benzoic acid O (1.0 g, 2.42 mmol) was dissolved in CH ₂ Cl ₂ (24 mL),
Cooled to 0 ° C. This solution was added to oxalyl chloride (420 μL, 4.84 mmol), DM
Treated with F (50 μL) and stirred at room temperature for 1 hour. The solvent was removed by centrifugal evaporation and the residual benzoyl chloride P was dried in vacuo for 2 hours to give a white solid.

A solution of compound 1 (384 mg, 1.21 mmol) in THF (12 mL) was cooled to 0 ° C. and treated with solid potassium hydride (192 mg, 3.64 mmol, 70% oil dispersion). The reaction was stirred at 0 ° C. for 30 minutes. Intermediate P is dissolved in THF (5 mL),
The above compound 1 anion was added dropwise. The mixture is stirred at 0 ° C. for a further 30 minutes,
It was then quenched with saturated aqueous NaHCO ₃ (30 mL). EtOAc (15 mL)
And the layers were separated. The organic layer was washed with brine (3 × 30 mL) and anhydrous Na ₂ SO ₄
And filtered through a sintered glass filter funnel and the solvent removed by centrifugal evaporation. The residue was purified by column chromatography on silica gel with a 0-20% gradient of E.
Purification was performed using tOAc / hexane as an eluent to obtain prodrug Q of dibenzyl phosphate as an orange solid.

Yield: 422 mg, 50%. M / Z: 712.24 [M + 1]. ¹ H NMR (300
MHz, CDCl ₃ ): δ (ppm) 1.91 (s, 3H); 2.12 (s, 3H); 3
. 77 (s, 3H); 4.85 to 4.96 (d, 4H); 5.33 to 5.44 (d, 2H)
); 5.71 (s, 1H); 5.79 (s, 1H); 6.79 (s, 1H); 7.06 (
s, 1H); 7.11 to 7.35 (m, 15H); 7.41 to 7.68 (m, 4H).

Dibenzyl phosphate prodrug Q (100 mg, 0.14 mmol) in wet CH ₂
Dissolved in Cl ₂ (2 mL) and treated with TFA (2 mL). The mixture was refluxed for 3 hours and the solvent was removed by centrifugal evaporation. Phosphate prodrug 67 was purified by RP-HPLC on a _C18 column with a gradient of H ₂ O / CH ₃ CN as mobile phase (pH 9).

M / Z: 532.17 [M + 1]. ¹ H NMR (300 MHz, DMSO-d ₆ ):
δ (ppm) 2.30 (s, 3H); 2.40 (s, 3H); 3.98 (s, 3H); 4
. 65-4.81 (d, 2H); 6.24 (s, 1H); 6.43 (s, 1H); 6.4
8-6.60 (d, 2H); 7.05-7.18 (m; 2H); 7.19-7.3 (m,
1H); 7.33 (s, 1H); 7.39-7.46 (d, 2H); 7.46-7.54
(M, 1H); 7.54-7.64 (m, 1H); 7.64-7.75 (m, 1H).

[Solubility of Compound 1 Tartrate, Compound 1 Mesylate, and Compound 66]
To determine if the compound is soluble in the solution, the solution was added to a 0.2 μM polytetrafluoroethylene filter (Whatman, Inc. (Whatman).
Inc. ) [Clifton, NJ, USA] and compound concentration in the filtrate was measured by LC / MS and compared to the expected concentration. A compound was considered soluble in solution if the concentration of the compound in the filtrate was the expected concentration ± 15%.

Detection of Compound 1 tartrate, Compound 1 mesylate, or Compound 66 by LC / MS was performed by Waters Alliance ™ 4-component gradient HPLC pump (Waters, Milford, Mass., USA). Where)
And a ZQ2000 single quadrupole mass spectrometer (Waters, Milford, Mass., USA). The column used was XTerra® MS C18: 50 × 2.1 mm, 3.5 mm column (
20 ° C.). Samples were injected and separated under the following conditions. Mobile phase “A” consists of 5 mM ammonium formate, 0.1% formic acid in water, and mobile phase “B” is 5 in methanol.
It consisted of mM ammonium formate and 0.1% formic acid. A linear gradient was applied as follows: 0 to 1 minute, 94% “A” and 6% “B”; 1 to 4 minutes, 6% to 100% “B”;
4-8 minutes, 100% “B”: 8-9 minutes, 100% “B” -6% “B”; 9-12 minutes, 94
% “A” and 6% “B”. The mass spectrometer system consisted of a Waters ZQ2000 single quadrupole mass spectrometer (Waters, Milford, Mass., USA) equipped with an electrospray ionizer (ES). The mass detector was operated in positive ion mode (ES +) and selected ion recording mode (SIR). The compounds were detected at m / z equal to their respective molecular weights + 1.

Compound 1 has poor solubility in water. Solubility of Compound 1 Tartrate is 0.1 mg / mL
be equivalent to. Compound 1 mesylate is the preferred salt because it was 4 times more soluble (0.4 mg / mL). This increase in solubility has a positive effect on the storage stability of the formulated Compound 1. 0.6 mg / mL of compound 1 tartrate, 9.6% polyethylene glycol 3
A formulation comprising 00, 0.4% polysorbate 20, and 5% dextrose is compound 1
There is a tendency to settle in 1 hour after preparation so that 40-50% of the tartrate salt remains in the 0.2 μM filter. In contrast, a formulation containing 0.6 mg / mL of Compound 1 mesylate, 9.6% polyethylene glycol 300, 0.4% polysorbate 20, and 5% dextrose shows signs of precipitation 72 hours after preparation. There wasn't. Therefore, Compound 1 mesylate represents a significant improvement because it sufficiently increases the stability of the formulation and can therefore be used clinically.

The addition of phosphoric acid increases the solubility of poorly soluble compounds. Phosphate prevents the compound from entering the cell, but phosphate can be gradually removed by alkaline phosphatase in the plasma. Therefore, a compound to which phosphoric acid has been added is a prodrug. For example, Compound 66 is a phosphate prodrug of Compound 1, and the solubility of Compound 66 in water is 10 m.
g / mL, 100 times higher than Compound 1 tartrate. In vivo, prodrugs have time to disperse throughout the blood because phosphate is not immediately removed by alkaline phosphatase. As the phosphate group is removed, it is time for the released drug to be distributed in the tissue. Therefore, this poorly soluble drug does not precipitate in the blood. The advantage of a prodrug is that it can be formulated as an aqueous solution at a high concentration so that it can be dispensed with a relatively small amount of injection.

[Phosphate prodrug compound 6 in vitro by alkaline phosphatase
Conversion from 6 to biologically active counterparts]
The conversion of phosphate prodrugs to biologically active drugs by calf intestinal alkaline phosphatase and human placental alkaline phosphatase was measured in vitro using purified enzymes. Purified calf intestine alkaline phosphatase (Roche Diagnostics Inc., Laval, Quebec, Canada) or human placental alkaline phosphatase (Sigma-Aldrich Canada Ltd.) [Oakville, Ontario, Canada] at a concentration of 0.02 U / 100 μL, 15 μM Compound 66, 20 mM Tris-HCl, pH 7.4 and 0.9%
It was added to the solution containing NaCl. This solution was incubated for 30, 60, or 120 minutes. 15 μM compound 66, 20 mM Tris-HCl, pH 7.4 and 0.9
A solution containing% NaCl was used as a standard solution (time = 0 minutes). In each solution, an equal volume (
100 μL) of ice-cold acetonitrile was added, then the mixture was vortexed and transferred to a glass vial. A standard concentration curve of prodrug and active drug was generated using 10 mM Tris-
Prepared in HCl, pH 7.4, 0.45% NaCl, and 50% acetonitrile. All samples were analyzed immediately by LC / MS.

As shown in FIGS. 4 and 5, both calf intestinal alkaline phosphatase and human placental alkaline phosphatase convert a portion of prodrug compound 66 present in solution to compound 1 of the active drug within 2 hours. Can do.

[Effects of Compound 1 Mesylate and Compound 66, respectively, on Prostate Tumor Cell Growth In Vivo]
Human prostate adenocarcinoma PC3 cells were collected from the American Type Culture Collection (ATCC
) Purchased from. It was confirmed that these cells were not infected with mycoplasma. Cells are maintained at 37 ° C. under 5% carbon dioxide (CO 2) in Roswell Park Memorial Institute medium (RPMI) supplemented with 10% fetal bovine inactivated serum and 1% penicillin-streptomycin-L-glutamine. It was done. For prostate tumor induction, cells were grown to <70% confluency in complete medium and then trypsin (Bio-Whittaker, Rockland, MD, USA).
). The cells are then centrifuged and phosphate buffered saline solution (PBS
) Twice and resuspended in PBS to give a cell concentration of 1.5 × 10 ⁶ /0.1
mL. The PC3 cells are then treated as a suspension of tumor cells (100
1.5 × 10 ⁶ cells in μL PBS), SCID mice (Charles River Laboratories, Wilmington, Mass., USA), implanted subcutaneously on the flank 11 days later Ten days after transplantation, the mice were randomly divided into groups of 10 mice based on each tumor size, so that the average tumor size in each group was comparable, relative tumor size and volume. Was calculated as follows: length (cm) × [width (cm)
] ^2/2. The mice were then given 5 subsequent intravenous (tail vein) injections that consisted of 200 μL of 9.6% polyethylene glycol 300, 0.4% polysorbate 20, and 5% dextrose (vehicle only). ) 4.84 μmol / Kg of compound 1 mesylate (formulated in 9.6% polyethylene glycol 300, 0.4% polysorbate 20, and 5% dextrose), 4.84 μmol / Kg of compound 66 ( Prodrug) (formulated in 5% dextrose), or 14.51 μmol / Kg of compound 66 (
Prodrug) (formulated in 5% dextrose). As shown in FIG. 6, Compound 1 mesylate and Compound 66 (prodrug) significantly reduced prostate tumor growth in mice.

[Effects of compounds on cancer cell viability in vitro]
In order to further demonstrate the anticarcinogenic effects of the tricyclic heterocyclic compounds of the present invention, several compounds were synthesized and the effects of the compounds on cancer cell viability were described in Example 2 of the present application. H
This was demonstrated by measuring cellular ATP levels in 1299 and C33A cancer cell lines. As shown in Table 4, these compounds had the effect of reducing cellular ATP levels in H1299 and C33A cancer cell lines. In any case, these compounds are believed to have utility in the in vivo methods of the invention, ie, in the treatment and prevention of cancer and viral infection, respectively. This cell-based assay is in v
Although considered to be an indicator of anti-carcinogenic activity in ivo, it is noted that it is not just a useful assay for evaluating the anti-carcinogenic activity of the tricyclic heterocyclic compounds of the present invention. Should be. Furthermore, the antiviral and other biological activities of the compounds of the invention can be determined and evaluated in other assay systems known to those skilled in the art.

It should also be noted that for use as a pharmaceutical in vivo, efficacy is not the only factor to be considered for assessing the suitability of a compound as a drug. Other factors,
For example, toxicity and bioavailability also determine the suitability of a compound as a drug. Toxicity and bioavailability can also be tested in any assay system known to those skilled in the art.

The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended to be illustrative of certain aspects of the invention, and any functionally equivalent embodiment of the present invention Is in range. Indeed, in addition to the embodiments shown and described herein, various modifications of the present invention will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

  A number of references have been cited, the entire disclosures of which are incorporated herein by reference.

Graph comparing the effect of Compound 1 tartrate on the viability of cancer cell lines H1299 and C33A and normal cell lines HMEC and MRC5. Measurements were taken 72 hours after treatment with 0.5 μM Compound 1 tartrate. Graph showing the time course of body weight of SCID mice after treatment with 4 mg / kg dose of cisplatin or 4.5 mg / kg dose of Compound 1 tartrate. Line-□-represents the control group, line -Δ- represents the cisplatin-treated group, and line-◯-represents the compound 1 tartrate-treated group. Graph showing changes in tumor volume of SCID mice transplanted with C33A human cervical cancer cells and treated with 4 mg / kg dose of cisplatin or 4.5 mg / kg dose of Compound 1 tartrate. Line-□-represents the control group, line -Δ- represents the cisplatin-treated group, and line-◯-represents the compound 1 tartrate-treated group. FIG. 6 is a graph showing the conversion of compound 66 (prodrug) to compound 1 (drug) over time in the presence of purified human placental alkaline phosphatase. FIG. 6 is a graph showing the conversion of compound 66 (prodrug) to compound 1 (drug) over time in the presence of purified calf intestinal phosphatase. Graph showing the effect of compound 1 mesylate and compound 66 (prodrug) on the growth of prostate cancer in mice.

Claims (29)

The following formula:

Or a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —N (R ₁ ) —;
Q ₂ is —C (R ₃ );
Q ₃ is —C (R ₅ );
Q ₄ is —C (R ₉ );
R ₁ is —Y _m (R _a ), where —R _a is —H, —OH, —C _{1 to} C ₈ alkyl, —C _{2 to} C ₈ alkenyl, —C _{2 to} C _8. alkynyl, -C ₃ -C ₁₂ cycloalkyl, - phenyl, - naphthyl, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, - _{O-C (O) R 14} , -C (O) (CH 2) n -R 14, -O-C (O) OR 14, -O-C (O) NHR 14, -O-C (O) _{N (R 14) 2, -C} (O) N (R 14) 2, -C (O) OR 14, be a -C (O) NH R _14;
R ₂ is —H, —C ₁ -C ₈ alkyl or —OH;
R ₃ and R ₄ are independently —Y _m (R _b ), where R _b is —H, halogen, —NH ₂ , —CN, —NO ₂ , —SH, —N ₃ , —C ₁ -C ₈ alkyl, -O- (C _{1 ~C 8} alkyl), - C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, - phenyl, - naphthyl, - 3- to 9-membered heterocycle, —OR ₁₄ , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O—C (O) R ₁₄ , —C (O) (CH ₂ ) _n— R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ either a _{-C (O) oR 14, -C} (O) NH R 14, or R ₃ and R ₄ together, each form a ring of 5-membered to 9-membered together with the carbon atom bonded ,
Provided that when Q ₃ is —C (R ₅ ) — and m = 0, R ₅ is not H;
R ₅ is —C ₁ -C ₈ alkyl or —O— (C ₁ -C ₈ alkyl);
R ₆ is —H;
R ₇ is —Y _m (R _c ), wherein —R _c is —C ₁ -C ₈ alkyl, —O— (C ₁ -C ₈ alkyl), —O-benzyl, —OH, _{-NH 2, -NH (C 1 ~C} 5 _{alkyl), - N (C 1 ~C} 5 alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N (naphthyl ) ₂ , —CN, —NO ₂ , —N ₃ , —C _{2 to} C ₈ alkynyl, —OR ₁₄ , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O—C (O ) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) _{2, -C (O) N (} R 14) 2, -C (O) OR 14, it is a -C (O) NH R _14;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 1 ~C 8 alkyl, - (C ₁ -C _{8 alkyl) -OH, -O- (C 1 ~C} 8 alkyl), - C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, - Phenyl, -naphthyl, -3 to 9-membered heterocycle, -OR ₁₄ , -O (CH ₂ ) _n OR ₁₄ , -C (O) R ₁₄ , -O-C (O) R ₁₄ , -C ( O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O) OR ₁₄ , Be a -C (O) NH R _14;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where —R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl. , -NH (C ₁ ~C _{5 alkyl), - N (C 1 ~C} 5 alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N (naphthyl) _{2, -C (O) NH (C 1} ~C 5 alkyl), - C (O) N (C 1 ~C 5 _{alkyl) 2, -NHC (O) (} C 1 ~C 5 alkyl), - NHC (= NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O —C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N _{(R 14) 2, -C (} O) N (R 14) 2, -C (O) R _14, or is -C (O) NH R _14, together with R ₁₁ and R _12, respectively form a heterocyclic ring of 5-membered to 9-membered together with the carbon atom bonded;
Each R ₁₄ independently represents —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; or be a -C ₂ -C ₈ alkynyl;
Y each independently, -C ₁ -C ₈ alkylene -, - C ₂ -C ₈ alkenylene - or -C ₂ -C ₈ alkynylene -; and
each m is independently 0 or 1; and each n is independently an integer in the range of 0-6,
Each said -C ₁ -C ₈ alkyl is unsubstituted or represented by one or more halogen, -NH ₂ , -OH, -O- (C ₁ -C ₈ alkyl), phenyl, or naphthyl groups Has been replaced,
Each said -C ₂ -C ₈ alkyl and -C ₂ -C ₈ alkynyl is unsubstituted or substituted by a phenyl or naphthyl group,
Each said -O- benzyl and - phenyl is substituted with unsubstituted or -OH, halogen, -N (CH _{3) 2} or -O, (C ₁ ~C ₈ alkyl). The compound according to claim 1, wherein Q ₁ is —NH—. Q ₄ are a -CH-, R ₂ is -H, the compounds according to claim 2. R _4, R ₈ and R ₁₀ to R ₁₃ is a -H, the compounds according to claim 3. Q ₂ is —C (C ₁ -C ₈ alkyl) —, Q ₃ is —C (C ₁ -C ₈ alkyl) —, and R ₇ is —O— (C ₁ -C ₈ alkyl) —. The compound of claim 4 , wherein The compound is
2- [5- (4-Iodo-3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole,
2- [4-methoxy-5- (3-methoxy-1H-pyrrol-2-ylmethylene) -5H-pyrrol-2-yl] -1H-indole,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -5,6-dimethoxy-1H-indole,
5-bromo-2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrole-2-yl] -3- (4-phenyl-piperazin-1-ylmethyl) -1H -Indole,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -3-morpholin-4-ylmethyl-1H-indole,
2-({2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -3-hydroxymethyl-4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-ylmethyl } -Amino) -ethanol,
[5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-2- (3-methylaminomethyl-1H-indol-2-yl) -5H-pyrrol-3-yl]- methanol,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole,
{2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -thiophen-3-yl- Methanone,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-ethoxy-5H-pyrrol-2-yl] -3- (2-morpholin-4-yl-ethyl) -1H- Indole,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -5-methoxy-1H-indole,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -3- (2-pyrrolinidin-2-yl-ethyl) -1H -Indole,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole-3-carboxylic acid,
5- {2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -5-oxo- Pentanoic acid methyl ester,
3-iodo-2- [5- (4-iodo-3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole,
{2- [5- (4-Ethoxyoxalyl-3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -oxo -Acetic acid ethyl ester,
5-bromo-2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indole-1-carboxylic acid tert-butyl ester;
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-ethoxy-5H-pyrrol-2-yl] -3- (2-pyrrolidin-2-yl-ethyl) -1H- Indole,
{2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] 1H-indol-3-yl}-(5-pyridin-2- Yl-thiophen-2-yl) -methanone,
1- {2- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -ethanone,
{2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -isoxazol-3-yl- Methanone,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole-3-carbaldehyde,
{2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -furan-3-yl- Methanone,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -5-methoxy-indole-1-carboxylic acid tert-butyl ester;
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-ethoxy-5H-pyrrol-2-yl] -1H-indole,
(2- {2- [3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-ethoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -ethyl) -dimethyl-amine ,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indole,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -3- (2-morpholin-4-yl-ethyl) -1H -Indole,
2- {2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -ethyl)- Dimethyl-amine,
2- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -5- (1H-indol-2-yl) -2H-pyrrol-3-ol,
{2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-3-yl} -methanol,
1- {2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-yl} -2-methyl-pyropane- 1-on,
Carboxylic acid tert-butyl ester 2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indol-4-yl ester,
Carboxylic acid tert-butyl ester 2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-4-yl ester,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indole-1-carboxylic acid dimethylamide;
2- {2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-yl} -ethanol,
{2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-yl} -phenyl-methanone,
3- {5- [5- (1H-indol-2-yl) -3-methoxy-pyrrol-2-ylidenemethyl] -2,4-dimethyl-1H-pyrrol-3-yl} -propan-1-ol,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -5-fluoro-1H-indole,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -6-fluoro-1H-indole,
6-chloro-2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indole,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indole-3-carboxylic acid (3-hydroxy-propyl)- Amide,
2- {5- [1- (3,5-dimethyl-1H-pyrrol-2-yl) -ethylidene] -4-methoxy-5H-pyrrol-2-yl} -1H-indole,
2- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -5- (1H-indol-2-yl) -2H-pyrrol-3-ol,
[2- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -5- (1H-indol-2-yl] -2H-pyrrol-3-yloxy] -acetic acid ethyl ester,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4- (3-methoxy-benzyloxy) -5H-pyrrol-2-yl] -1H-indole,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indole-1-carboxylic acid (4-benzyloxy-phenyl) -amide ,
2- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indole-1-carboxylic acid (4-dimethylamino-phenyl) -amide ,
(4-Bromo-phenyl)-{2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-yl}- Methanone,
4- {2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-ylmethyl} -phenol,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indol-6-ol,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -1H-indol-4-ol,
2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-isopropoxy-5H-pyrrol-2-yl] -1H-indol-4-ol,
6- [5- (3,5-Dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -5H- [1,3] dioxolo [4,5-f] indole ,
[2- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -5- (1H-indol-2-yl) -2H-pyrrol-3-yl]-(4-methoxy-phenyl) -amine,
2,2-dimethyl-propionic acid 2- [5- (3,5-dimethyl-1H-pyrrol-2-ylmethylene) -4-methoxy-5H-pyrrol-2-yl] -indol-1-ylmethyl ester,
{2- [5- (3,5-dimethyl -1H- pyrrol-2-ylmethylene) -4-methoxy -5H- pyrrol-2-yl] - indol-1-yl} - acetic acid, and 3- {5 -[5- (1H-indol-2-yl) -3-methoxy-pyrrol-2-ylidenemethyl] -2,4-dimethyl-1H-pyrrol-3-yl} -propionic acid methyl ester,
And the compound of claim 1 selected from pharmaceutically acceptable salts thereof. The following formula:

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof. The following formula:

Or a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —NH—;
Q ₄ is —C (R ₉ ) —;
R ₆ is —H, halogen, —OH, —NH ₂ , —C ₁ -C ₈ alkyl or —O— (C ₁ -C ₈ alkyl);
R ₇ and R ₈ are independently —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 1 -C ₈ alkyl, -O- (C ₁ ~C ₈ alkyl), - (C ₁ ~C ₈ alkyl) -OH, -O- benzyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, - phenyl, - naphthyl, -C ₇ -C ₁₂ (phenyl) alkyl, -C ₇ -C ₁₂ (naphthyl) alkyl, -C ₇ -C ₁₂ (phenyl) alkenyl, -C ₇ -C ₁₂ (naphthyl) alkenyl, -C _{7 ~C 12} (phenyl) alkynyl, -C _{7 ~C 12} (naphthyl) Arni , -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) (CH ₂ ) _n— R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R _{14 ) 2, -C (O) OR} 14, it is a -C (O) NH R _14;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl. , -NH (C ₁ ~C _{5 alkyl), - N (C 1 ~C} 5 alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N (naphthyl) _{2, -C (O) NH (C 1} ~C 5 alkyl), - C (O) N (C 1 ~C 5 _{alkyl) 2, -NHC (O) (} C 1 ~C 5 alkyl), - NHC (= NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O —C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N _{(R 14) 2, -C (} O) N (R 14) 2, -C (O) R _14, or is -C (O) NH R _14, together with R ₁₁ and R _12, respectively form a heterocyclic ring of 5-membered to 9-membered together with the carbon atom bonded;
Each R ₁₄ independently represents —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; or be a -C ₂ -C ₈ alkynyl;
Y each independently, -C ₁ -C ₈ alkylene -, - C ₂ -C ₈ alkenylene - or -C ₂ -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.] The following formula:

Or a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —NH—;
Q ₄ is —CH— ;
R ₆ is —H;
R ₇ and R ₈ are independently —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 1 -C ₈ alkyl, -O- (C ₁ ~C ₈ alkyl), - (C ₁ ~C ₈ alkyl) -OH, -O- benzyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, - phenyl, - naphthyl, -C ₇ -C ₁₂ (phenyl) alkyl, -C ₇ -C ₁₂ (naphthyl) alkyl, -C ₇ -C ₁₂ (phenyl) alkenyl, -C ₇ -C ₁₂ (naphthyl) alkenyl, -C _{7 ~C 12} (phenyl) alkynyl, -C _{7 ~C 12} (naphthyl) alkyl Le, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) ( CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R _{14) 2, -C (O)} OR 14, it is a -C (O) NH R _14;
R ₉ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are independently —Y _m (R _e ), where R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl. , -NH (C ₁ ~C _{5 alkyl), - N (C 1 ~C} 5 alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N (naphthyl) _{2, -C (O) NH (C 1} ~C 5 alkyl), - C (O) N (C 1 ~C 5 _{alkyl) 2, -NHC (O) (} C 1 ~C 5 alkyl), - NHC (= NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N ₃ , a -3 to 9 membered heterocyclic ring, —OR ₁₄ , —O (CH ₂ ) _n OR ₁₄ , —C (O) R ₁₄ , —O —C (O) R ₁₄ , —C (O) (CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N _{(R 14) 2, -C (} O) N (R 14) 2, -C (O) R _14, or is -C (O) NH R _14, together with R ₁₁ and R _12, respectively form a heterocyclic ring of 5-membered to 9-membered together with the carbon atom bonded;
Each R ₁₄ independently represents —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; or be a -C ₂ -C ₈ alkynyl;
Y each independently, -C ₁ -C ₈ alkylene -, - C ₂ -C ₈ alkenylene - or -C ₂ -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.] The following formula:

Or a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —NH—;
Q ₄ is —CH—;
R ₆ is —H;
R ₇ and R ₈ are independently —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 1 -C ₈ alkyl, -O- (C ₁ ~C ₈ alkyl), - (C ₁ ~C ₈ alkyl) -OH, -O- benzyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, - phenyl, - naphthyl, -C ₇ -C ₁₂ (phenyl) alkyl, -C ₇ -C ₁₂ (naphthyl) alkyl, -C ₇ -C ₁₂ (phenyl) alkenyl, -C ₇ -C ₁₂ (naphthyl) alkenyl, -C _{7 ~C 12} (phenyl) alkynyl, -C _{7 ~C 12} (naphthyl) alkyl Le, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) ( CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R _{14) 2, -C (O)} OR 14, it is a -C (O) NH R _14;
R ₉ is —Y _m (R _e ), where R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -C (O) NH} (C 1 ~C 5 alkyl) , —C (O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC (═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N _3, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) ( CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R _{14) 2, -C (O)} OR 14, it is a -C (O) NH R _14;
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are —H;
Each R ₁₄ independently represents —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; or be a -C ₂ -C ₈ alkynyl;
Y each independently, -C ₁ -C ₈ alkylene -, - C ₂ -C ₈ alkenylene - or -C ₂ -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.] The following formula:

Or a pharmaceutically acceptable salt thereof, wherein
Q ₁ is —NH—;
Q ₄ is —CH—;
R ₆ is —H;
R ₇ is —O— (C ₁ -C ₈ alkyl)-;
R ₈ is —Y _m (R _d ), where —R _d is —H, —OH, halogen, amino, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -CN, -NO 2,} -N 3, -C 1 ~C 8 alkyl, -O- (C ₁ ~C ₈ alkyl), - (C ₁ ~C ₈ alkyl) -OH, -O- benzyl, -C ₂ -C ₈ alkenyl, -C ₂ -C ₈ alkynyl, -C ₃ -C ₁₂ cycloalkyl, -phenyl, -naphthyl, -C ₇ -C ₁₂ (phenyl) alkyl, -C ₇ -C ₁₂ (naphthyl) alkyl, -C ₇ -C ₁₂ (phenyl) alkenyl, -C ₇ -C ₁₂ ( naphthyl) alkenyl, -C ₇ -C ₁₂ (phenyl) alkynyl, -C ₇ -C ₁₂ (naphthyl) alkynyl, -3-membered to 9 _{Heterocyclic, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) (CH 2) n -R 14, —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R ₁₄ ) ₂ , —C (O ) OR _14, be a -C (O) NH R _14;
R ₉ is —Y _m (R _e ), where R _e is —H, halogen, —NH ₂ , C ₁ -C ₈ alkyl, —NH (C ₁ -C ₅ alkyl), —N (C ₁ -C ₅ alkyl) _2, -NH (phenyl), - N (phenyl) _2, -NH (naphthyl), - N _{(naphthyl) 2, -C (O) NH} (C 1 ~C 5 alkyl) , —C (O) N (C ₁ -C ₅ alkyl) ₂ , —NHC (O) (C ₁ -C ₅ alkyl), —NHC (═NH ₂ ⁺ ) NH ₂ , —CN, —NO ₂ , N _3, -3-membered to 9-membered _{heterocycle, -OR 14, -O (CH 2} ) n OR 14, -C (O) R 14, -O-C (O) R 14, -C (O) ( CH ₂ ) _n —R ₁₄ , —O—C (O) OR ₁₄ , —O—C (O) NHR ₁₄ , —O—C (O) N (R ₁₄ ) ₂ , —C (O) N (R _{14) 2, -C (O)} OR 14, it is a _{-C (O) NH R 1 4} ;
R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are —H;
Each R ₁₄ independently represents —H, —C _{1 to} C ₈ alkyl, —C _{3 to} C ₁₂ cycloalkyl, —phenyl, —naphthyl, a −3 to 9 membered heterocycle, —C _{2 to} C ₈ alkenyl; or be a -C ₂ -C ₈ alkynyl;
Y each independently, -C ₁ -C ₈ alkylene -, - C ₂ -C ₈ alkenylene - or -C ₂ -C ₈ alkynylene -; and
m is each independently 0 or 1; and n is each independently an integer ranging from 0 to 6.]   A pharmaceutical composition for the treatment of cancer, comprising a pharmaceutically acceptable carrier or vehicle and an effective amount of a compound of formula (Ia) according to claim 1.   The pharmaceutical composition according to claim 12, wherein the cancer is selected from cervical cancer, non-small cell lung cancer, breast cancer, colorectal cancer, and melanoma. 13. A pharmaceutical composition according to claim 12, wherein in the compound of formula Ia, Q < ₁ > is -NH-. In the compound of formula Ia, Q ₁ is —NH—, Q ₂ is —C (R ₃ ) —, Q ₃ is —C (R ₅ ) —, Q ₄ is —CH—, R ₂ and R ₆ are -H, pharmaceutical composition according to claim 12. In the compound of formula Ia, Q ₁ is —NH—, Q ₂ is —C (R ₃ ) —, Q ₃ is —C (R ₅ ) —, Q ₄ is —CH—, _{R 2, R 4, R 6} , R 8 and R ₁₀ to R ₁₃ is -H, pharmaceutical composition according to claim 12. In the compound of formula Ia, Q ₁ is —NH—, Q ₂ is —C (C ₁ -C ₈ alkyl)-, Q ₃ is —C (C ₁ -C ₈ alkyl)-, ₄ is —CH—, R ₇ is —O— (C ₁ -C ₈ alkyl)-, and R ₂ , R ₄ , R ₆ , R ₈ and R ₁₀ -R ₁₃ are —H. Item 13. A pharmaceutical composition according to Item 12.   The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is administered in combination with another chemotherapeutic agent.   The pharmaceutical composition according to claim 18, characterized in that it is administered in combination with another therapeutic agent.   A pharmaceutical composition for the treatment of cancer, comprising an effective amount of the compound according to claim 7 or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier or vehicle. object.   21. The pharmaceutical composition according to claim 20, wherein the cancer is selected from cervical cancer, non-small cell lung cancer, breast cancer, colorectal cancer, and melanoma. A process for preparing a compound of formula (Ia) according to claim 1 comprising
In the presence of an organic solvent and a protonic acid, at a time and temperature sufficient to prepare a compound of formula (Ia) according to claim 1, formula (II):

A compound of formula (iv):

A method comprising contacting with a compound of:   23. The method of claim 22, wherein the organic solvent is an alcohol.   24. The method of claim 23, wherein the alcohol is methanol or ethanol.   The method according to claim 22, wherein the acid is an aqueous hydrochloric acid solution or an aqueous hydrobromic acid solution. A process for preparing a compound of formula (Ia) according to claim 1 comprising
(A) Formula (II) in the presence of a substantially anhydrous aprotic organic solvent:

And a compound of formula (v):

Wherein M is Li, Na, K, Rb or Cs.
And the formula (vi):

[Wherein M is defined as above]
Contacting for a time and at a temperature sufficient to prepare a compound of:
(B) a method comprising protonating a compound of formula (vi) with an H ⁺ donor for a time and at a temperature sufficient to prepare a compound of formula (Ia) according to claim 1.   27. The method of claim 26, wherein the aprotic solvent is tetrahydrofuran or diethyl ether.   8. The compound of claim 7, wherein the pharmaceutically acceptable salt is tartrate or mesylate.   13. The pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable salt is tartrate or mesylate.

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